17-hydroxyprogesterone ester-containing oral compositions and related methods

ABSTRACT

The present invention provides for bioavailable oral dosage forms containing esters of 17-hydroxyprogesterone as well as related methods. The oral dosage forms can be formulated for pregnancy support and can include a therapeutically effective amount of an ester of 17-hydroxyprogesterone and a pharmaceutically acceptable carrier. In another embodiment, a pharmaceutically acceptable oral dosage form for pregnancy support is provided. The pharmaceutically acceptable oral dosage can include a therapeutically effective amount of an ester of 17-hydroxyprogesterone and a pharmaceutically acceptable carrier. The oral dosage form can, when measured using a USP Type-II dissolution apparatus in 900 mL of deionized water with 0.5 (w/v) of sodium lauryl sulfate at 50 RPM at 37° C., release at least 20 wt % of the dose of the ester of 17-hydroxyprogesterone after 60 minutes, or in the alternative release at least 20 wt % more after 60 minutes than an equivalently dosed oral dosage form without the carrier.

PRIORITY DATA

This application is a continuation of U.S. patent application Ser. No.14/477,771, filed on Sep. 4, 2014, which is a continuation of U.S.patent application Ser. No. 13/193,571, filed on Jul. 28, 2011, nowissued as U.S. Pat. No. 8,951,996, each of which is incorporated hereinby reference.

FIELD OF THE INVENTION

The present invention relates to 17-hydroxyprogesterone ester containingcompositions, oral dosage forms thereof, and associated methods.Accordingly, this invention involves the fields of chemistry,pharmaceutical sciences, medicine and other health sciences.

BACKGROUND OF THE INVENTION

17-alpha hydroxyprogesterone (alternatively hereinafter referred to as17-hydroxyprogesterone or “17HP”) is a C-21 endogenous steroid hormoneproduced during the syntheses of glucocorticoids and sex steroids. Likeprogesterone, 17HP is a natural progestagen. It has been isolated fromboth adrenal glands and corpora lutea. Esters of 17HP are reported tohave progestogenic effects and hence, can be used for indicationsrelated to pregnancy support as well as non-pregnancy support in bothpre- and post-menopausal women. It is reported that 17HP, withoutesterification, has no progestational activity. However, the syntheticesters of 17HP such 17-hydroxyprogesterone acetate or17-alpha-hydroxyprogesterone caproate (also referred hereafter as 17hydroxyprogesterone caproate or 17 HPC) have been shown to exhibitmarked progestational activity when administered intramuscularly inanimal experiments. 17-Hydroxyprogesterone caproate is a commonly usedprogestin available for intramuscular injection to prevent Preterm Birth(alternatively hereinafter referred to as “PTB”). This syntheticcaproate ester is reportedly inactive when given by mouth but works as along-acting progestin when administered intramuscularly. The metabolismof 17HP and the metabolism of 17-hydroxyprogesterone caproate in thehuman female are not yet fully established. Data from humans and animalsindicate that intramuscularly administered 17-hydroxyprogesteronecaproate has more potent progestational effect on endometrium and islonger lasting than progesterone (alternatively hereinafter referred toas “P”). This may be due to more avid binding of 17-hydroxyprogesteronecaproate to the progesterone receptors (alternatively referred tohereinafter as “PR”) and placental glucocorticoid receptors(alternatively referred to hereinafter as “GR”) that could prevent anincrease of placental corticotropin releasing hormone which isassociated with onset of labor. 17-hydroxyprogesterone caproate isreportedly effective in providing luteal support in patients undergoingIVF-Embryo Transfer Cycles.

PTB is medically defined as delivery from 20 to 36 weeks of gestation.According to the 2009 Center for Disease Control Report, PTB occurs inabout 12.3% of births in the US alone translating to about half amillion PTBs annually. Spontaneous PTB accounts for approximately 70-80%of PTB. Of all the pregnancies in the US, one out of every eightlive-born infants is born preterm representing an increase of >18% since1990. Late pre-term birth between 35-36 weeks of gestation contributesto more than half of all PTBs. PTB is the primary cause of neonatalmorbidity and mortality. Mortality risk is three fold higher at 35-36weeks and morbidities such as respiratory distress requiring oxygen,temperature instability, hypoglycemia, jaundice, attention deficitdisorders, cerebral palsy, developmental delay, etc. are quite common.PTB related time and costs in intensive care are a major health, socialand economic issue with an average cost of PTB delivery amounting to upto 10× that of normal delivery.

Major risk factors implicated in PTB are as follows: History of previousspontaneous PTB (past obstetrics history), cervical length (<2.5 cm atmid pregnancy), presence of fetal fibronectin in vaginal secretions;multiple gestation, low maternal Body Mass Index (BMI), maternal race;maternal age (<17 and >35 years), and smoking. The prior history of atleast one PTB is a good indicator of future occurrence potential with17-50% recurrence potential and 28-70% recurrence potential with twoprevious PTBs. Benefits of prolonging pregnancy to full term withtherapeutic intervention include improved child survival as a functionof gestational age, and reduced neonatal hospital stay.

Intramuscular injection of 17-hydroxyprogesterone caproate is availablefor reducing the risk of PTB in women with singleton pregnancy andhistory of single spontaneous PTB. The injection marketed as Makena®(250 mg 17-hydroxyprogesterone caproate in 1 mL) mandates regular visitsto the doctor's office, as the typical treatment cycle consists of 16-20weeks of injection repeated every week. This therapy regimen couldresult increasing the patient's distress and/or anxiety in addition toincreasing the repeated travel risks for the patient and fetus. Theinjection therapy's interferences with the personal and familyactivities and disruption in professional life are also a majordisadvantage.

In addition, adverse events with injection of 17-hydroxyprogesteronecaproate (e.g. Makena®) at once weekly (every 7 days) the injection sitereactions (˜45%) such as urticaria, pruritis, swelling, nodule formationand pain at the site of injection have been reported as significant.

Esters of hydroxy progesterone such as acetate, caproate, undecanoateare more lipophilic than hydroxy progesterone. The active substance(17-hydroxyprogesterone caproate) in Makena® is known to be extremelyinsoluble in water (<20 ng/mL), and very lipophilic with ClogP of about5.7. Moreover, 17-hydroxyprogesterone caproate has the potential to bemetabolized in the presence of fetal and adult hepatocytes and is asubstrate for cytochrome inactivation such as CYP3A4 which is overlyexpressed in pregnant women (˜40% upregulation). Due to its extremelylow water solubility and a potential to be susceptible for first passhepatic inactivation oral delivery of long chain esters of 17HP hasremained a challenge. It is reported that there is no oral activity with17 hydroxyprogesterone caproate, an ester of 17 HP, (Saxton D J et. al.Reproductive Biology and Endocrinology 2004, 2:80; Greene M F, NJEM348:2453-2455). This could be likely due to very poor or no oralbioavailability of 17 HPC. Although much desired, to date thedevelopment of an orally active composition of long chain ester ofhydroxyl progesterone remains a significant unmet need. In addition,development of dosage forms that enable administration of lesser numberof dosage units per dose and/or at reduced frequency per day is mostoften desirable.

SUMMARY OF THE INVENTION

It has now been surprisingly found that esters of 17HP can beeffectively delivered orally to mammals. The pharmaceutical oralcompositions and dosage forms of the present inventions can provideeffective bioavailability of an ester of 17HP. Further, the compositionsand/or dosage forms disclosed herein provide effective releaseenhancement for 17 HP esters. We have also surprisingly found that anester of 17HP can be formulated into oral compositions and oral dosageforms thereof with higher percent w/w loading of the ester. For example,we have found that when one or more solubilizing agents such as forexample, benzyl alcohol, benzyl benzoate etc., is incorporated in thecomposition, a significant amount (i.e. greater than 12% w/w) of theester of 17HP can be solubilized in the composition or dosage form. Theincreased drug loading in the compositions and dosage forms of thecurrent inventions, can provide avid advantages including but notlimited to reduced size or volume of the unit dosage (i.e. tablet,capsule, syrup, elixir, beverage, etc.), reduced number of dosage unitsto be taken per single administration, improved patient compliance etc.,because patients typically can take fewer number of dosage units per dayin order to get a sufficient dose to provide the desired efficacy. In aseparate aspect, it was also surprisingly found that an effectivebioavailability of the ester of 17HP can be provided by the compositionsof the current inventions which when dispersed in an aqueous medium,provide clear or colloidal to hazy or unclear dispersions havingpartially or fully solubilized drug in the dispersions.

It was also found that the compositions of current invention enableproduction of solid dosage forms such as tablets, caplets, granules,beads, particulates etc., which can solve the drawbacks of having the17HP ester in a liquid solution form in the dosage unit. This eliminatesa number of undesirable inconveniences, such as specializedmanufacturing process and/or equipment, poor chemical and/or physicalstability of the ester typical to liquid solutions due to the nature ofthe ester or solvents used, and so-on.

All the oral dosage forms of the present inventions have the drug in theform of solution, suspension, particulates, etc., can be produced byconventional methods of processing and manufacture known in the art.

The present invention provides for compositions and oral dosage formscontaining esters of 17HP as well as related methods. The compositionsand oral dosage forms can be formulated to include a therapeuticallyeffective amount of an ester of 17HP and a pharmaceutically acceptablecarrier. In one embodiment, a pharmaceutically acceptable oral dosageform for pregnancy support and non-pregnancy support is provided. Thepharmaceutically acceptable oral dosage can include a therapeuticallyeffective amount of an ester of 17HP and a pharmaceutically acceptablecarrier. The oral dosage form can, when measured using a USP Type-IIdissolution apparatus in 900 mL of deionized water with 0.5%(w/v) ofsodium lauryl sulfate at 50 RPM at 37° C., release at least 20 wt % ofthe dose of the ester of 17HP after 60 minutes.

In yet a further embodiment, a pharmaceutically acceptable oral dosageform for pregnancy or non-pregnancy support is provided. Thepharmaceutically acceptable oral dosage can include a therapeuticallyeffective amount of an ester of 17HP and a pharmaceutically acceptablecarrier. The oral dosage form can, when measured using a USP Type-IIdissolution apparatus in 900 mL of deionized water with 0.5%(w/v) ofsodium lauryl sulfate at 50 RPM at 37° C., release at least 20 wt % more17HP ester after 60 minutes than an equivalently dosed oral dosage formwithout the carrier.

In some aspects, the oral dosage forms of the present invention can beused to treat pregnant female subjects who are at risk of preterm birth.Such methods of treatment may include the step of orally administeringto the female subject the oral pharmaceutical composition. In someaspects, the dosage amount is an amount sufficient to provide anintended therapeutic effect. In another embodiment, the oral dosageforms can be administered to subjects in need thereof. Theadministration of the oral dosage form can treat at least one conditionselected from preterm labor, preterm birth, infertility and miscarriage.The conditions and the relative treatment can be based on their primaryand secondary outcome measurements associated with the administration ofthe ester of 17HP.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a plot of the in vitro release profile of a17-hydroxyprogesterone caproate containing oral dosage form inaccordance with a certain embodiment of the present invention comparedto a carrier-free dose of 17-hydroxyprogesterone caproate.

FIG. 2 is a plot of the in vitro release profiles of17-hydroxyprogesterone containing oral dosage forms in accordance with acertain embodiment of the present invention.

FIG. 3 is a plot of the in vitro release profiles of17-hydroxyprogesterone containing oral dosage forms in accordance with acertain embodiment of the present invention.

Reference will now be made to the exemplary embodiments illustrated, andspecific language will be used herein to describe the same. It willnevertheless be understood that no limitation of the scope of theinvention is thereby intended.

DETAILED DESCRIPTION OF EXAMPLE EMBODIMENT(S)

Before the present oral dosage forms and methods for the delivery anduse of 17-hydroxyprogesterone esters are disclosed and described, it isto be understood that this invention is not limited to the particularprocess steps and materials disclosed herein, but is extended toequivalents thereof, as would be recognized by those ordinarily skilledin the relevant arts. It should also be understood that terminologyemployed herein is used for the purpose of describing particularembodiments only and is not intended to be limiting.

It should be noted that, the singular forms “a,” “an,” and, “the”include plural referents unless the context clearly dictates otherwise.Thus, for example, reference to “an excipient” includes reference to oneor more of such excipients, and reference to “the carrier” includesreference to one or more of such carriers.

Definitions

As used herein, “drug,” “active agent,” “bioactive agent,”“pharmaceutically active agent,” “therapeutically active agent” and“pharmaceutical,” may be used interchangeably to refer to an agent orsubstance that has measurable specified or selected physiologic activitywhen administered to a subject in a significant or effective amount. Itis to be understood that the term “drug” is expressly encompassed by thepresent definition as many drugs and prodrugs are known to have specificphysiologic activities. These terms of art are well-known in thepharmaceutical and medicinal arts. Further, when these terms are used,or when a particular active agent is specifically identified by name orcategory, it is understood that such recitation is intended to includethe active agent per se, as well as pharmaceutically acceptable salts,esters or compounds significantly related thereto, including withoutlimitation, prodrugs, active metabolites, isomers, and the like.

As used herein, the term “recurrent” is used to refer to a repeat orre-occurrence of at least one incidence like “miscarriage”, “pretermbirth” or “preterm labor” or “multifetal gestation” or any like medicalsituation in reference with or without same partner, with or withoutprevious live birth.

As used herein, the term “treatment” when used in conjunction with theadministration of a 17-hydroxyprogesterone ester, refers to theadministration of the 17-hydroxyprogesterone ester to subjects who areeither asymptomatic or symptomatic. In other words, “treatment” canrefer to the act of reducing or eliminating a condition (i.e. symptomsmanifested), or it can refer to prophylactic treatment, (i.e.administering to a subject not manifesting symptoms in order to preventtheir occurrence). Such prophylactic treatment can also be referred toas prevention of the condition, preventative action, preventativemeasures, etc.

As used herein, the term “ester” represents compounds produced byreaction between acids and alcohols with the elimination of water. Asdescribed herein, the term “ester” can also represent the class oforganic compounds corresponding to the inorganic salts formed from anorganic acid and an alcohol. In one aspect, the “ester of17-hydroxyprogesterone” can be the caproate ester, but can alsorepresent esters of the longer chain fatty acids such as undecanoic acidand higher, that typically get lymphatically absorbed and avoid firstpass hepatic metabolism for improved efficacy or safety.

As used herein, the terms “formulation” and “composition” are usedinterchangeably and refer to a mixture of two or more compounds,elements, or molecules. In some aspects the terms “formulation” and“composition” may be used to refer to a mixture of one or more activeagents with a carrier or other excipients. Furthermore, the term “dosageform” can include one or more formulation(s) or composition(s) providedin a format for administration to a subject. When any of the above termsis modified by the term “oral” such terms refer to compositions,formulations, or dosage forms formulated and intended for oraladministration to subjects.

The terms “pharmaceutically acceptable carrier” or “carrier” are usedinterchangeably and refer to a pharmaceutically acceptable substancethat enables a pharmaceutical composition and/or a dosage form of anester of 17-hydroxyprogesterone. Further, in some aspects, the carrieris an element or ingredient that can be varied for the alteration ofrelease rate and/or extent of the active agent, for example an ester of17-hydroxyprogesterone, from the composition and/or the dosage form. Inone aspect of the invention, a pharmaceutically acceptable carrier is acompound, or a mixture of compounds, that determines, controls, orcontributes, at least in part, to the release of an ester of17-hydroxyprogesterone from a pharmaceutical oral composition and/ordosage form, when tested using a USP Type II apparatus in about 900 mLof simulated intestinal fluid (according to USP, SIF, without enzyme)having 0.5% w/w sodium lauryl sulfate at about 37° C. and 50 rpm.

In another embodiment, the composition or dosage form provides a releaseof the ester of 17-hydroxyprogesterone such that when tested using a USPType II apparatus in about 900 mL of simulated intestinal fluid having0.5% w/w sodium lauryl sulfate at about 37° C. and 50 rpm, at least 20%more the ester of 17-hydroxyprogesterone is released after the first 60minutes compared to an equivalent dose an ester of17-hydroxyprogesterone oral dosage form without the pharmaceuticallyacceptable carrier. In another particular embodiment, the composition orthe dosage form releases at least 40% more of the ester of17-hydroxyprogesterone after the first 60 minutes compared to anequivalent dose an ester of 17-hydroxyprogesterone oral dosage formwithout the pharmaceutically acceptable carrier.

It should be noted that the release of the ester of17-hydroxyprogesterone from the composition or the dosage form can betested in a suitable solubilizing medium or a non-solubilizing aqueousmedium at about 37° C., in a USP Type II apparatus at 50 rpm. Forexample, aqueous medium can be water, simulated gastric fluid (SGF) withor without enzyme, simulated intestinal fluid (SIF) with or withoutenzyme, a hydro-alcoholic solution, a surfactant solution and the like.The aqueous medium can be used for the purpose of determining therelease rate and/or extent of the ester of 17-hydroxyprogesterone fromthe compositions or the dosage forms. The aqueous medium can be anon-solubilizing aqueous medium (for example, having low or nosurfactant in the medium) for the entire amount of the ester present inthe composition or the dosage form. In one embodiment, thenon-solubilizing aqueous medium can solubilize about 90% or less of theamount of ester present in the composition or dosage form. In anotherembodiment, the non-solubilizing aqueous medium can solubilize about 80%or less, about 70% or less, about 60% or less, about 50% or less, about30% or less, or about 20% or less of the total amount of the esterpresent in the composition or dosage form.

Conversely, in another embodiment the aqueous medium is capable ofsolubilizing substantially all of the ester of 17-hydroxyprogesteronepresent in the composition or dosage form. In one embodiment, theaqueous medium can solubilize at least about 90% of the amount of theester of 17-hydroxyprogesterone present in the composition or dosageform. In a particular embodiment the aqueous medium can solubilize about1.5 times or more, about 3 times or more, 5 times or more of the amountof the ester 17-hydroxyprogesterone present in the composition or dosageform.

As used herein, “subject” refers to a mammal that may benefit from theadministration of a drug composition or method of this invention.Examples of subjects include humans, and may also include other animalssuch as horses, pigs, cattle, dogs, cats, rabbits, and aquatic mammals.In one specific aspect, a subject is a human. In another aspect, thesubject is a female. In yet another aspect, the oral dosage form of thecurrent invention is for a female requiring pregnancy support.

The term “oral administration” represents any method of administrationin which an active agent can be administered by swallowing, chewing, orsucking or drinking an oral dosage form. Such solid or liquid oraldosage forms are traditionally intended to substantially release and ordeliver the active agent in the gastrointestinal tract beyond the mouthand/or buccal cavity. Examples of solid dosage forms includeconventional tablets, multi-layer tablets capsules, caplets, etc., whichdo not substantially release the drug in the mouth or in the oralcavity.

As used herein, the terms “release” and “release rate” are usedinterchangeably to refer to the discharge or liberation of a substance,including without limitation a drug, from the dosage form into asurrounding environment such as an aqueous medium either in vitro or invivo.

As used herein, the term “lipophilic” when used in combination with bothsolid and liquid lipophilic additives (alternatively referred tohereinafter as “LA”), refers to additives that “love oil” and generallyhave poor or no solubility in water. “Lipophilic surfactants”(alternatively referred to hereinafter as “LS”) refer to lipophilicadditives that have HLB values of 10 or less, preferably between 2 to10. Conversely, the term “hydrophilic,” when used in combination withboth solid and liquid hydrophilic additives (alternatively referred tohereinafter as “HA”), refers to additives that “love water”, andgenerally have average or good solubility in water. “Hydrophilicsurfactants” (alternatively referred to hereinafter as “HS”) arehydrophilic additives that have significant surface active property andthat have HLB values of more than 10.

As used herein, the term “lipid” or lipid substance” when used inconnection, with various compounds, refers to fatty acid (unlessotherwise specified, having chain length greater than C₆) or fatty acidesters or glycerides of fatty acid esters, mixtures thereof andderivatives thereof, although not including salts thereof.

In some aspects of the present invention, the release of the drug may becontrolled release. As used herein, the term “controlled release”represents the release of the drug from the dosage form according to apredetermined profile. In some aspects, the controlled release selectedcan be, intermediate, delayed, extended, sustained, pulsatile, gastric,enteric or colonic. In another aspect, combinations of theaforementioned release profiles may be used in order to achieve specificdelivery results, such as an immediate release followed by a delayedand/or a sustained release of the active agent.

As used herein, a composition or dosage form provides “immediaterelease” when greater than about 90% of the drug is released after thefirst 30 minutes, in a USP simulated gastric fluid (SGF) with or withoutenzyme.

As used herein, the term “pregnancy support” when used to describe thefunctionality of the oral compositions or dosage forms of the presentinvention, can refer to providing exogenous progestational support frominception through birth including, but not limited to preterm birth,preterm labor, and miscarriage. The pregnancy support can provideimproved quality of the pregnancy for the pregnant woman, the fetus, orboth. Further, pregnancy support can also include increased fertilityfor a woman trying to become pregnant.

As used herein, the term “non-pregnancy” support when used to describethe functionality of the oral compositions or dosage forms of thepresent invention, can refer to conditions that require exogenoussupplementation of a progestogen agent to a non-pregnant subject, suchas a non-pregnant woman, including but not limited to, delaying orpreventing the occurrence of undesirable pregnancy, preventing ortreating conditions due to progesterone deficiencies such as amenorrhea,fibroids, contraception, postpartum lactation suppression, treatment ofdysfunctional uterine bleeding, endometriosis, endometrial hyperplasia,cervical hyperplasia, hormone replacement therapy, treatment ofhypoventilation, prevention and treatment of osteoporosis, management ofbreast, hypothyroidism, migraine headaches, pemporomandibular jointsyndrome, catamenial epilepsy, endometrial, and/or renal carcinomas. Inone embodiment, the term “non-pregnancy” support when used to describethe functionality of the oral compositions or dosage forms of thepresent invention can refer to conditions that require exogenoussupplementation of the progestogen agent of the invention to a malehuman for example, to effect contraception, to counter estogenicactivity, etc. It should be noted that the present compositions anddosage forms of the ester of the 17-hydroxyprogesterone may beadministered alone or in combination with other therapy. In anotherembodiment, the current invention compositions and dosage forms of theester of the 17-hydroxyprogesterone may be used to supplement, augment,mitigate, treat, cure or prevent, or for providing prophylaxis in asubject in need thereof.

As used herein, an “effective amount” or a “therapeutically effectiveamount” of a drug refers to a non-toxic, but sufficient amount of thedrug, to achieve therapeutic results in treating a condition for whichthe drug is known to be effective. It is understood that variousbiological factors may affect the ability of a substance to perform itsintended task. Therefore, an “effective amount” or a “therapeuticallyeffective amount” may be dependent in some instances on such biologicalfactors. Further, while the achievement of therapeutic effects may bemeasured by a physician or other qualified medical personnel usingevaluations known in the art, it is recognized that individual variationand response to treatments may make the achievement of therapeuticeffects a somewhat subjective decision. The determination of aneffective amount is well within the ordinary skill in the art ofpharmaceutical sciences and medicine. See, for example, Meiner andTonascia, “Clinical Trials: Design, Conduct, and Analysis,” Monographsin Epidemiology and Biostatistics, Vol. 8 (1986), incorporated herein byreference.

As used herein, the term “about” is used to provide flexibility to anumerical range endpoint by providing that a given value may be “alittle above” or “a little below” the endpoint. As used herein, aplurality of items, structural elements, compositional elements, and/ormaterials may be presented in a common list for convenience. However,these lists should be construed as though each member of the list isindividually identified as a separate and unique member. Thus, noindividual member of such list should be construed as a de factoequivalent of any other member of the same list solely based on theirpresentation in a common group without indications to the contrary.

Concentrations, amounts, levels and other numerical data may beexpressed or presented herein in a range format. It is to be understoodthat such a range format is used merely for convenience and brevity andthus should be interpreted flexibly to include not only the numericalvalues explicitly recited as the limits of the range, but also toinclude all the individual numerical values or sub-ranges encompassedwithin that range as if each numerical value and sub-range is explicitlyrecited. As an illustration, a numerical range of “about 1 to about 5”should be interpreted to include not only the explicitly recited valuesof about 1 to about 5, but also include individual values and sub-rangeswithin the indicated range. Thus, included in this numerical range areindividual values such as 2, 3, and 4 and sub-ranges such as from 1-3,from 2-4, and from 3-5, etc., as well as 1, 2, 3, 4, and 5,individually. This same principle applies to ranges reciting only onenumerical value as a minimum or a maximum. Furthermore, such aninterpretation should apply regardless of the breadth of the range orthe characteristics being described.

Invention

Reference will now be made in detail to preferred embodiments of theinvention. While the invention will be described in conjunction with thepreferred embodiments, it will be understood that it is not intended tolimit the invention to those preferred embodiments. To the contrary, itis intended to cover alternatives, variants, modifications, andequivalents as may be included within the spirit and scope of theinvention as defined by the appended claims.

During pregnancy, it has been shown that serum progestogen, includingprogesterone and 17-hydroxyprogesterone levels are decreased in thepregnant female in cases of intrauterine death, premature labor,threatened premature labor, premature rupture of membranes, amnionitisand abruption of placenta. As discussed above, it has been discoveredthat esters of 17-hydroxyprogesterone have potential for use inpregnancy to treat and or prevent the following conditions oroccurrences: spontaneous abortion in women who have had previousspontaneous abortion, history of recurrent spontaneous abortion,previous stillbirth, previous premature delivery (<37 weeks), previouspremature (<37 weeks) rupture of membranes or PROM, previous pregnancyrelated hypertension or toxemia, previous abruption of placenta,threatened premature labor or cerclage, multiple pregnancy, primary orsecondary infertility, congenital uterine anomaly or any other conditionwhere endogenous progestogen (e.g. progesterone) levels are lower thanin normal pregnancy.

Primary and secondary outcome measures can be used to determine the needfor and/or the effectiveness of ester of 17-hydroxyprogesteronesupplementation therapy for pregnancy related support to a particularsubject and its direct or indirect effect on the neonates. Typicalprimary and secondary outcome measures for preterm birth and pretermlabor include, without limitation,

Primary Outcome Measures (Maternal):

-   -   1. Perinatal mortality    -   2. Preterm birth (less than 32 weeks' gestation)    -   3. Preterm birth (less than 34 weeks' gestation)    -   4. Preterm birth (less than 37 weeks' gestation)    -   5. Major neuro-developmental handicap at childhood follow up        Secondary Outcome Measures (Maternal):    -   1. Threatened preterm labor    -   2. Pre-labor spontaneous rupture of membranes    -   3. Adverse drug reaction    -   4. Pregnancy prolongation (interval between randomization and        birth)    -   5. Mode of birth    -   6. Number of antenatal hospital admissions    -   7. Satisfaction with the therapy    -   8. Use of tocolysis        Secondary Outcome Measures (Infant):    -   1. Birth before 37 completed weeks    -   2. Birth before 34 completed weeks    -   3. Birth before 32 completed weeks    -   4. Birth before 28 completed weeks    -   5. Birth weight less than the third centile for gestational age    -   6. Birth weight less than 2500 grams    -   7. Apgar score of less than seven at five minutes    -   8. Respiratory distress syndrome    -   9. Use of mechanical ventilation    -   10. Duration of mechanical ventilation    -   11. Intraventricular hemorrhage—grades III or IV    -   12. Periventricular leucomalacia    -   13. Retinopathy of prematurity    -   14. Retinopathy of prematurity—grades III or IV    -   15. Chronic lung disease    -   16. Necrotizing enterocolitis    -   17. Neonatal sepsis    -   18. Fetal death    -   19. Neonatal death    -   20. Admission to neonatal intensive care unit    -   21. Neonatal length of hospital stay    -   22. Teratogenic effects (including virilisation in female        infants)        Secondary Outcome Measures (Child):    -   1. Major sensorineural disability (defined as any of legal        blindness, sensorineural deafness requiring hearing aids,        moderate or severe cerebral palsy, or developmental delay or        intellectual impairment)    -   2. Developmental delay    -   3. Intellectual impairment    -   4. Motor impairment    -   5. Visual impairment    -   6. Blindness    -   7. Deafness    -   8. Hearing impairment    -   9. Cerebral palsy    -   10. Child behavior    -   11. Child temperament    -   12. Learning difficulties    -   13. Growth assessments at childhood follow up (weight, head        circumference, length, skin fold thickness)        In-vitro Fertilization        1. Primary Outcome Measures:    -   1.1. Pregnancy Rate    -   1.2. Live birth    -   1.3. Ongoing pregnancy rate    -   1.4. Clinical pregnancy, defined as ultrasound evidence of fetal        heart activity at 6-8 weeks of gestation    -   1.5. Fetus Vitality measured by heart beat    -   1.6. Rate of complete abortion 24-48 hrs after receiving medical        treatment for early pregnancy failure.        2. Secondary Outcome Measures:    -   2.1. Clinical pregnancy    -   2.2. Cycle Cancellation Rates    -   2.3. Number of Oocytes Generated    -   2.4. Number of Embryos Generated    -   2.5. Serum hormonal evaluation    -   2.6. Follicular fluid evaluation    -   2.7. Peak estradiol level    -   2.8. Ampules of gonadotropins required during ovarian        stimulation    -   2.9. Number of days of ovarian stimulation    -   2.10. Number of oocytes retrieved    -   2.11. Number of embryos transferred    -   2.12. Number of embryos frozen    -   2.13. Embryo grade    -   2.14. Implantation rate    -   2.15. Miscarriage rate    -   2.16. Pregnancy outcome    -   2.17. rate of complete abortion at one week, time to expulsion        of products of conception, correlation of abortion rates to        serum 17-hydroxyprogesterone levels and type of pregnancy        failure, number of bleeding days and patient satisfaction    -   2.18. Ovarian Response [assessed upon completion of the        controlled ovarian stimulation and the egg collection        procedures]        Miscarriage        1. Primary Outcomes    -   1.1. Miscarriage    -   1.2. Early miscarriage up to 12 weeks    -   1.3. Miscarriage later than 12 weeks and less than 23 weeks    -   1.4. Cytokine ratio IFN/IL-10    -   1.5. Clinical pregnancy rate at 8 weeks and 12 weeks of        pregnancy        2. Secondary Outcomes    -   2.1. Mother        -   a. Pain relief (threatened miscarriage)        -   b. Severity of ‘morning sickness’—intensified headache        -   c. nausea, breast tenderness        -   d. reported thromboembolic events        -   e. Thrombolytic events        -   f. depression;        -   g. admission to special care unit        -   h. subsequent fertility.        -   i. PIBF level        -   j. Uterine contraction frequency    -   2.2. Child        -   a. Preterm birth;        -   b. stillbirth;        -   c. neonatal death;        -   d. low birthweight less than 2500 g        -   e. fetal genital abnormalities;        -   f. teratogenic effects (impairing normal fetal development);        -   g. admission to special care unit.    -   2.3. General        -   a. Intrauterine fetal death        -   b. Still birth        -   c. Fetal        -   d. Exploratory analysis of pregnancy outcome by monitoring            biochemical and clinical pregnancy parameters, weekly            evaluation of serum progesterone        -   e. live birth rate, cycle cancellation rate, rate of            spontaneous abortion, rate of biochemical pregnancy, rate of            ectopic pregnancy

Several biomarkers have been implicated in predicting preterm birth(PTB). Among symptomatic women, the likelihood ratio (LR+) for theprediction of PTB is known to be greater than 10 using amniotic fluid(AF) interleukin-6 (IL-6), AF Ureaplasma urealyticum, as well as amulti-marker consisting of cervical IL-6, cervical IL-8, and cervicallength (CL). The LR+ is also known to be between 5 and 10 for serumC-reactive protein (CRP). An LR+ between 2.5 and 5 was recorded forserum corticotropin-releasing hormone (CRH), cervical IL-6, serumrelaxin.

In asymptomatic women, AFU urealyticum and a multimarker consisting offive individual markers [fFN, CL, serum alpha-fetoprotein (AFP), serumalkaline phosphatase, and serum granulocyte colony-stimulating factor(G-CSF)] predict PTB with an LR+ greater than 10. The LR+ was between 5and 10 for serum relaxin and CL. LRs+ recorded for serum alkalinephosphatase, salivary estriol, serum CRH, serum G-CSF, cervical IL-6, AFIL-6, cervical fFN, AFP, and chlamydia all ranged between 2.5 and 5.Finally, an LR+ below 2.5 has been documented for serum ferritin, serumCRP, BV, and cervical ferritin.

Miscarriages and possible miscarriages can be categorized in severalways: A) threatened or possible miscarriage—when any bleeding from theuterus occurs before 20 weeks, but the cervix is closed and the fetus isalive; B) Inevitable abortion or miscarriage (inevitable—meaning itcannot be stopped, particularly if there is bleeding from the uterus andthe cervix is opening prior to 20 weeks, but neither the fetus norplacenta have passed out of the woman's body)—the membranes around thefetus may or may not have ruptured (broken); C) Incomplete abortion ormiscarriage—when a portion of the fetus or placenta has passed out ofthe uterus prior to 20 weeks gestation while some of the placenta orfetus remains in the uterus; D) Complete miscarriage—complete expulsionof all the membranes around the fetus and the placenta and the cervixcloses prior to 20 weeks; E) Missed abortion or miscarriage—death of thefetus prior to 20 weeks gestation with neither the fetus nor theplacenta having been expelled from the uterus; F) Recurrentmiscarriage—a woman is said to have recurrent miscarriage after she hasalready had two or more miscarriages in a row; G) Blighted ovum oran-embryonic gestation—occurs when a gestational sac forms inside theuterus, but no fetus is present after seven weeks.

Threatened miscarriage, as demonstrated by low endogenous progesteroneor 17-hydroxyprogesterone, or vaginal bleeding with or without abdominalcramps within 26 weeks of conception, is a common complication ofpregnancy. It occurs in about 20% of recognized pregnancies. Risk ofmiscarriage is increased in older women and those with a history ofmiscarriage.

It has been shown that low serum levels of progestogen (progesterone or17 HP) or human chorionic gonadotropin (hCG) are a risk factor formiscarriage. Threatened miscarriage causes considerable stress andanxiety for a pregnant woman. Because esters of 17-hydroxyprogesteroneinteract with the progesterone receptor, it is believed that treatmentwith esters of 17-hydroxyprogesterone can be designed based onprogesterone levels. One diagnostic criterion is low serum progesterone,but levels vary widely during early pregnancy and any later decline maybe attributed to a dysfunctioning placenta. Nevertheless, luteal supportis widely used for the management of threatened miscarriage. Firsttrimester pregnancies show risk of miscarriage with declining serumprogesterone levels. Levels of <5 ng/ml were associated with aspontaneous miscarriage in 86% of cases compared with only 8% at levelsof 20-25 ng/ml. A threshold value of 14 ng/ml has been reported todifferentiate between the viable and non-continuing pregnancies. Othermaternal serum biomarkers such as Tumor marker CA-125, Inhibin A,Anandamide and progesterone induced blocking factor (PIBF) are also goodindicators of miscarriage risk.

In one embodiment, the compositions of the present invention areintended to provide an increase in the baseline endogenous progesteroneand/or 17-hydroxyprogesterone. In a particular embodiment the increasein the baseline endogenous progesterone can be greater than 10%.Progestogens also have a direct pharmacological effect by reducing thesynthesis of prostaglandins, thereby relaxing uterine smooth musculatureand preventing inappropriate contractions that may result inmiscarriage.

Although the oral dosage forms and methods of the present invention canbe used in most female subjects, patients most suitable for receivingoral 17-hydroxyprogesterone ester of this invention are the ones thathave one or more of the following conditions, symptoms, and/or needs: 1)are in need of an anti-inflammatory; 2) are progesterone deficient withbase line progesterone in early (first trimester) pregnancy ofC_(avg)<14 ng/ml or baseline progesterone levels, C_(avg) of less than50 ng/ml in late (second and third trimester) pregnancy; 3) have geneticvariation of the SERPINH1 gene that cause to produce a reduced amount ofthe protein, collagen, which may lead to weakened fetal membranes; 4)have a genetic variant of the Prolylcarboxypeptidase gene associatedwith preeclampsia; 5) have certain bacterial infections (bacterialvaginosis) including Ureaplasma urealyticum, Mycoplasma hominis,Gardnerella vaginalis, and Peptostreptococcus and Bacteroides species;6) have abnormal amniotic fluid metabolome (the sum of all metabolicprocesses occurring in the amniotic fluid) indicating risk forprematurity; 7) have had above average total phthalate exposure; 8)abnormal prepregnancy body mass index; 9) have inflammatory milieu ofthe vagina in early pregnancy; 10) have increased maternal plasmaurocortin levels; 11) show increased uterine activity as noted by HomeUterine Activity Monitoring; 12) test positive to salivary estriollevels predicting preterm delivery; 13) show alarming fetal FibronectinScreening (fFS) results; 14) show unusual cervical shortening relativeto gestational age as measured by cervical ultrasonography, ortransvaginal ultrasound or digital examination with/without use ofCervilenz™; 15) show unusual maternal serum bio markers such as Tumourmarker CA-125, or Inhibin A, or Anandamide or Progesterone InducedBlocking factor (PIBF); 16) have unbalanced ratio of Th-1 cytokines toTh-2 cytokines such as IFN to IL-10.

Besides maintaining pregnancy, other potential uses of the ester of17-hydroxyprogesterone containing oral dosage forms of the presentinvention include, but are not limited to: a) preventing estrogendominance; b) stimulating new bone formation and prevent/reverseosteoporosis; c) providing the precursor for adrenal cortex hormones(corticosteroids); d) treating variety of skin problems such as acne inadult women, seborrhea, rosacea, psoriasis, and keratosis; e) promotingmyelin sheath production to protect nerve fibers and speed nervesignals; f) managing depression that accompany PMS, menopause,postpartum depression, etc.; g) protecting from brain/spinal cordinjury, stroke, and/or hemorrhage.

In one embodiment, the present invention provides for oral dosage formscontaining esters of 17-hydroxyprogesterone as well as related methods.The oral dosage forms can be formulated for pregnancy support and caninclude a therapeutically effective amount of an ester of17-hydroxyprogesterone and a pharmaceutically acceptable carrier. Theoral dosage form can, when measured using a USP Type-II dissolutionapparatus in 900 mL of deionized water with 0.5 (w/v) of sodium laurylsulfate at 50 RPM at 37° C., release at least 20 wt % of the dose of theester of 17-hydroxyprogesterone after 60 minutes. In yet a furtherembodiment, the oral dosage form can, when measured using a USP Type-IIdissolution apparatus in 900 mL of deionized water with 0.5 (w/v) ofsodium lauryl sulfate at 50 RPM at 37° C., release at least 20 wt % more17-hydroxyprogesterone ester after 60 minutes than an equivalently dosedoral dosage form without the carrier.

A number of 17-hydroxyprogesterone esters can be used in thecompositions and oral dosages of the present invention. Examples ofspecific acceptable esters of 17-hydroxyprogesterone include withoutlimitation, acetate esters of 17-hydroxyprogesterone, caproate esters of17-hydroxyprogesterone, undecanoate esters of 17-hydroxyprogesterone,and the like and combinations thereof. Other pharmacologically activeand acceptable esters of 17-hydroxyprogesterone may also be prepared andused in accordance with the embodiments of the present invention so longas they provide the desired support in pregnancy and/or non-pregnancyconditions.

The ester of 17-hydroxyprogesterone can be present in the compositionsand oral dosage forms of the present disclosure in a variety of forms.In one embodiment, the ester of 17-hydroxyprogesterone can be present inparticulate form. In one embodiment, the ester of 17-hydroxyprogesteronecan be present in particulate form. The particulate form can have a meandiameter of about 50 μm or less. The particulate form can have a meandiameter of about 25 μm or less. In another embodiment, the particulateform can have a mean diameter of about 1 μm or less. In anotherembodiment, the ester of 17-hydroxyprogesterone can be present in afully solubilized form. In another embodiment, the ester of17-hydroxyprogesterone can be present in a partially solubilized form.In another embodiment, a portion of the ester of 17-hydroxyprogesteronepresent in the composition and/or dosage form can be present inparticulate or unsolubilzied form. In some embodiments, the ester of17-hydroxyprogesterone can be present in both solubilized form as wellas in particulate form.

In some embodiments, the carrier of the compositions or oral dosageforms of the present invention can act to facilitate the delivery,release, and/or bioavailability of the ester of 17-hydroxyprogesterone.In certain aspects, the carrier can be one or a mixture of two or morecompounds. The carrier can include at least one of a lipophilic and/or ahydrophilic component additive. The lipophilic and hydrophilic additivesthat can be used in the compositions of the invention can be selectedfrom a variety of classes of the pharmaceutical aids including, but notlimited to, absorbents, acids, adjuvants, anticaking agent, antitackingagents, antifoamers, anticoagulants, antimicrobials, antioxidants,antiphlogistics, astringents, antiseptics, bases, binders, bufferants,chelating agents, sequestrants, celluloses, coagulants, coating agents,colorants, dyes, pigments, complexing agents, crystal growth regulators,denaturants, desiccants, drying agents, dehydrating agents, diluents,disintegrants, dispersants, emollients, emulsifiers, encapsulants,enzymes, extenders, fillers, flavor masking agents, flavorants,fragrances, gelling agents, glidants hardeners, stiffening agents,humectants, lubricants, moisturizers, pH control agents, plasticizers,soothing agents, demulcents, retarding agents, spreading agents,stabilizers, suspending agents, sweeteners, thickening agents,consistency regulators, surfactants, opacifiers, polymers,preservatives, antigellants, rheology control agents, softeners,solubilizers; solvents tonicifiers, viscosity modulators UV absorbers,or combinations thereof. In some embodiments additives from multipleclasses or types can be used.

Non-limiting examples of compounds that can form all or a part of thecarrier are set forth in the following lists which have been organizedin general categories. It is to be understood that the categories arenot intended to limit the particular carrier compounds, but are simplypresent for ease of organization and presentation. With this in mind,example carrier compounds can include one or more of the following:

Triglycerides such as Aceituno oil; Almond oil; Arachis oil; Babassuoil; Blackcurrant seed oil; Borage oil; Canola oil (Lipex 108 (Abitec));Castor oil; Cocoa butter; Coconut oil (Pureco 76 (Abitec)); Coffee seedoil); Corn oil; Cottonseed oil; Crambe oil; Cuphea species oil; Eveningprimrose oil; Grapeseed oil; Groundnut oil; Hemp seed oil; Illipebutter; Kapok seed oil; Linseed oil; Menhaden oil; Mowrah butter;Mustard seed oil; Oiticica oil; Olive oil; Palm oil; Palm kernel oil;Peanut oil; Poppy seed oil; Rapeseed oil; Rice bran oil; Safflower oil;Sal fat; Sesame oil; Shark liver oil; Shea nut oil; Soybean oil;Stillingia oil; Sunflower oil; Tall oil; Tea sead oil; Tobacco seed oil;Tung oil (China wood oil): Vernonia oil; Wheat germ oil; Hydrogenatedcastor oil (Castorwax); Hydrogenated coconut oil (Pureco 100 (Abitec));Hydrogenated cottonseed oil (Dritex C (Abitec)); Hydrogenated palm oil(Dritex PST (Abitec); Softisan154 (Huls)); Hydrogenated soybean oil(Sterotex HM NF (Abitec); Dritex S (Abitec)); Hydrogenated vegetable oil(Sterotex NF (Abitec): Hydrokote M (Abitec)); Hydrogenated cottonseedand caster oil (Sterotex K (Abitec)); Partially hydrogenated soybean oil(Hydrokote AP5 (Abitec)); Partially soy and cottonseed oil (Apex B(Abitec)); Glyceryl tributyrate (Sigma); Glyceryl tricaproate (Sigma);Glyceryl tricaprylate (Sigma); Glyceryl tricaprate (Captex 1000(Abitec)); Glyceryl trundecanoate (Captex 8227 (Abitec)); Glyceryltrilaurate (Sigma); Glyceryl trimyristate (Dynasan 114 (Huls)); Glyceryltripalmitate (Dynasan 116 (Huls)); Glyceryl tristearate (Dynasan 118(Huls)); Glyceryl triarcidate (Sigma); Glyceryl trimyristoleate (Sigma);Glyceryl tripalmitoleate (Sigma); Glyceryl trioleate (Sigma); Glyceryltrilinoleate (Sigma); Glyceryl tricaprylate/caprate (Captex 300(Abitec); Captex 355 (Abitec); Miglyol 810 (Huls); Miglyol 812 (Huls));Glyceryl tricaprylate/caprate/laurate (Captex 350 (Abitec)); Glyceryltricaprylate/caprate/linoleate (Captex 810 (Abitec); Miglyol 818(Huls)); Glyceryl tricaprylate/caprate/stearate (Softisan 378 (Huls);(Larodan); Glyceryl tricaprylate/laurate/stearate (Larodan); Glyceryl1,2-caprylate-3-linoleate (Larodan); Glyceryl 1,2-caprate-3-stearate(Larodan); Glyceryl 1,2-laurate-3-myristate (Larodan); Glyceryl1,2-myristate-3-laurate (Larodan); Glyceryl 1,3-palmitate-2-butyrate(Larodan); Glyceryl 1,3-stearate-2-caprate (Larodan); Glyceryl1,2-linoleate-3-caprylate (Larodan), mixtures and derivatives thereof.Fractionated triglycerides, modified triglycerides, synthetictriglycerides, and mixtures of triglycerides are also within the scopeof the invention.

PEG-Fatty Acid Monoester Surfactants (listed as compound name (commoncommercial product name (supplier) (HLB)): PEG 4-100 monolaurate (CrodetL series (Croda) (>9)); PEG 4-100 monooleate (Crodet O series (Croda)(>8)); PEG 4-100 monostearate (Crodet S series (Croda), Myrj Series(Atlas/ICI) (>6)); PEG 400 distearate (Cithrol 4DS series (Croda)(>10)); PEG 100, 200, 300 monolaurate (Cithrol ML series (Croda) (>10));PEG 100, 200, 300 monooleate (Cithrol MO series (Croda) (>10)); PEG 400dioleate (Cithrol 4DO series (Croda) (>10)); PEG 400-1000 monostearate(Cithrol MS series (Croda) (>10)); PEG-1 stearate (Nikkol MYS-1EX(Nikko), Coster K1 (Condea) (2)); PEG-2 stearate (Nikkol MYS-2 (Nikko)(4)); PEG-2 oleate (Nikkol MYO-2 (Nikko) (4.5)); PEG-4 laurate (Mapeg®200 ML (PPG), Kessco® PEG 200 ML (Stepan), LIPOPEG 2 L (LIPO Chem.)(9.3)); PEG-4 oleate (Mapeg® 200 MO (PPG), Kessco® PEG 200 MO (Stepan)(8.3)); PEG-4 stearate (Kessco® PEG 200 MS (Stepan), Hodag 20 S(Calgene), Nikkol MYS-4 (Nikko) (6.5)); PEG-5 stearate (Nikkol TMGS-5(Nikko) (9.5)); PEG-5 oleate (Nikkol TMGO-5 (Nikko) (9.5)); PEG-6 oleate(Algon OL 60 (Auschem SpA), Kessco® PEG 300 MO (Stepan), Nikkol MYO-6(Nikko), Emulgante A6 (Condea) (8.5)); PEG-7 oleate (Algon OL 70(Auschem SpA) (10.4)); PEG-6 laurate (Kessco® PEG300 ML (Stepan)(11.4)); PEG-7 laurate (Lauridac 7 (Condea) (13)); PEG-6 stearate(Kessco® PEG300 MS (Stepan) (9.7)); PEG-8 laurate (Mapeg® 400 ML (PPG),LIPOPEG 4DL (Lipo Chem.) (13)); PEG-8 oleate (Mapeg® 400 MO (PPG),Emulgante A8 (Condea) (12)); PEG-8 stearate (Mapeg® 400 MS (PPG), Myrj45 (12)); PEG-9 oleate (Emulgante A9 (Condea) (>10)); PEG-9 stearate(Cremophor S9 (BASF) (>10)); PEG-10 laurate (Nikkol MYL-10 (Nikko),Lauridac 10 (Croda) (13)); PEG-10 oleate (Nikkol MYO-10 (Nikko) (11));PEG-12 stearate (Nikkol MYS-10 (Nikko), Coster K100 (Condea) (11));PEG-12 laurate (Kessco® PEG 600 ML (Stepan) (15)); PEG-12 oleate(Kessco® PEG 600 MO (Stepan) (14)); PEG-12 ricinoleate (CAS #9004-97-1)(>10)); PEG-12 stearate (Mapeg® 600 MS (PPG), Kessco® PEG 600 MS(Stepan) (14)); PEG-15 stearate (Nikkol TMGS-15 (Nikko), Koster K15(Condea) (14)); PEG-15 oleate (Nikkol TMGO-15 (Nikko) (15)); PEG-20laurate (Kessco® PEG 1000 ML (Stepan) (17)); PEG-20 oleate (Kessco® PEG1000 MO (Stepan) (15)); PEG-20 stearate (Mapeg® 1000 MS (PPG), Kessco®PEG 1000 MS (Stepan), Myrj 49 (16)); PEG-25 stearate (Nikkol MYS-25(Nikko) (15)); PEG-32 laurate (Kessco® PEG 1540 ML (Stepan) (16));PEG-32 oleate (Kessco® PEG 1540 MO (Stepan) (17)); PEG-32 stearate(Kessco® PEG 1540 MS (Stepan) (17)); PEG-30 stearate (Myrj 51 (>10));PEG-40 laurate (Crodet L40 (Croda) (17.9)); PEG-40 oleate (Crodet 040(Croda) (17.4)); PEG-40 stearate (Myrj 52, Emerest® 2715 (Henkel),Nikkol MYS-40 (Nikko) (>10)); PEG-45 stearate (Nikkol MYS-45 (Nikko)(18)); PEG-50 stearate (Myrj 53 (>10)); PEG-55 stearate (Nikkol MYS-55(Nikko) (18)); PEG-100 oleate (Crodet 0-100 (Croda) (18.8)); PEG-100stearate (Myrj 59, Ariacel 165 (ICI) (19)); PEG-200 oleate (Albunol 200MO (Taiwan Surf.) (>10)); PEG-400 oleate (LACTOMUL (Henkel), Albunol 400MO (Taiwan Surf.) (>10)); PEG-600 oleate (Albunol 600 MO (Taiwan Surf.)(>10)); and combinations thereof.

PEG-Fatty Acid Diesters (listed as compound name (common commercialproduct name (supplier) (HLB)): PEG-4 dilaurate (Mapeg®200 DL (PPG),Kessco® PEG 200 DL (Stepan), LIPOPEG 2-DL (Lipo Chem.) (7)); PEG-4dioleate (Mapeg® 200 DO (PPG), (6)); PEG-4 distearate (Kessco® 200 DS(Stepan) (5)); PEG-6 dilaurate (Kessco® PEG 300 DL (Stepan) (9.8));PEG-6 dioleate (Kessco® PEG 300 DO (Stepan) (7.2)); PEG-6 distearate(Kessco® PEG 300 DS (Stepan) (6.5)); PEG-8 dilaurate (Mapeg® 400 DL(PPG), Kessco® PEG 400 DL (Stepan), LIPOPEG 4 DL (Lipo Chem.) (11));PEG-8 dioleate (Mapeg® 400 DO (PPG), Kessco® PEG 400 DO (Stepan),LIPOPEG 4 DO (Lipo Chem.) (8.8)); PEG-8 distearate (Mapeg® 400 DS (PPG),CDS 400 (Nikkol) (11)); PEG-10 dipalmitate (Polyaldo 2PKFG (>10));PEG-12 dilaurate (Kessco® PEG 600 DL (Stepan) (11.7)); PEG-12 distearate(Kessco® PEG 600 DS (Stepan) (10.7)); PEG-12 dioleate (Mapeg® 600 DO(PPG), Kessco® 600 DO (Stepan) (10)); PEG-20 dilaurate (Kessco® PEG 1000DL (Stepan) (15)); PEG-20 dioleate (Kessco® PEG 1000 DO (Stepan) (13));PEG-20 distearate (Kessco® PEG 1000 DS (Stepan) (12)); PEG-32 dilaurate(Kessco® PEG 1540 DL (Stepan) (16)); PEG-32 dioleate (Kessco® PEG 1540DO (Stepan) (15)); PEG-32 distearate (Kessco® PEG 1540 DS (Stepan)(15)); PEG-400 dioleate (Cithrol 4DO series (Croda) (>10)); PEG-400distearate (Cithrol 4DS series (Croda) (>10)); and combinations thereof.

PEG-Fatty Acid Mono- and Di-ester Mixtures (listed as compound name(common commercial product name (supplier) (HLB)): PEG 4-150 mono,dilaurate (Kessco® PEG 200-6000 mono, dilaurate (Stepan))); PEG 4-150mono, dioleate (Kessco® PEG 200-6000 mono, dioleate (Stepan))); PEG4-150 mono, distearate (Kessco® 200-6000 mono, distearate (Stepan)), andcombinations thereof.

Polyethylene Glycol Glygerol Fatty Acid Esters (listed as compound name(common commercial product name (supplier) (HLB)): PEG-20 glyceryllaurate (Tagat® L (Goldschmidt) (16)); PEG-30 glyceryl laurate (Tagat®L2 (Goldschmidt) (16)); PEG-15 glyceryl laurate (Glycerox L series(Croda) (15)); PEG-40 glyceryl laurate (Glycerox L series (Croda) (15));PEG-20 glyceryl stearate (Capmul® EMG (ABITEC), (13)); (Aldo® MS-20 KFG(Lonza))); PEG-20 glyceryl oleate (Tagat® 0 (Goldschmidt) (>10)); PEG-30glyceryl oleate (Tagat® 02 (Goldschmidt) (>10)); and combinationsthereof.

Alcohol-oil Transesterification Products: (listed as compound name(common commercial product name (supplier) (HLB)): PEG-3 castor oil(Nikkol CO-3 (Nikko) (3)); PEG-5, 9, and 16 castor oil (ACCONON CAseries (ABITEC) (6-7)); PEG-20 castor oil (Emalex C-20 (Nihon Emulsion),Nikkol CO-20 TX (Nikko) (11)); PEG-23 castor oil (Emulgante EL23 (>10));PEG-30 castor oil (Emalex C-30 (Nihon Emulsion), Alkamuls® EL 620(Rhone-Poulenc), Incrocas 30 (Croda) (11)); PEG-35 castor oil (CremophorEL and EL-P (BASF), Emulphor EL, Incrocas-35 (Croda), Emulgin RO 35(Henkel))); PEG-38 castor oil (Emulgante EL 65 (Condea))); PEG-40 castoroil (Emalex C-40 (Nihon Emulsion), Alkamuls® EL 719 (Rhone-Poulenc)(13)); PEG-50 castor oil (Emalex C-50 (Nihon Emulsion) (14)); PEG-56castor oil (Eumulgin® PRT 56 (Pulcra SA) (>10)); PEG-60 castor oil(Nikkol CO-60TX (Nikko) (14)); PEG-100 castor oil (Thornley (>10));PEG-200 castor oil (Eumulgin® PRT 200 (Pulcra SA) (>10)); PEG-5hydrogenated castor oil (Nikkol HCO-5 (Nikko) (6)); PEG-7 hydrogenatedcastor oil (Simusol® 989 (Seppic), Cremophor WO7 (BASF) (6)); PEG-10hydrogenated castor oil (Nikkol HCO-10 (Nikko) (6.5)); PEG-20hydrogenated castor oil (Nikkol HCO-20 (Nikko) (11)); PEG-25hydrogenated castor oil (Simulsol® 1292 (Seppic), Cerex ELS 250 (AuschemSpA) (11)); PEG-30 hydrogenated castor oil (Nikkol HCO-30 (Nikko) (11));PEG-40 hydrogenated castor oil (Cremophor RH 40 (BASF), Croduret(Croda), Emulgin HRE 40 (Henkel) (13)); PEG-45 hydrogenated castor oil(Cerex ELS 450 (Auschem Spa) (14)); PEG-50 hydrogenated castor oil(Emalex HC-50 (Nihon Emulsion) (14)); PEG-60 hydrogenated castor oil(Nikkol HCO-60 (Nikko); Cremophor RH 60 (BASF) (15)); PEG-80hydrogenated castor oil (Nikkol HCO-80 (Nikko) (15)); PEG-100hydrogenated castor oil (Nikkol HCO-100 (Nikko) (17)); PEG-6 corn oil(Labrafil® M 2125 CS (Gattefosse) (4)); PEG-6 almond oil (Labrafil® M1966 CS (Gattefosse) (4)); PEG-6 apricot kernel oil (Labrafil® M 1944 CS(Gattefosse) (4)); PEG-6 olive oil (Labrafil® M 1980 CS (Gattefosse)(4)); PEG-6 peanut oil (Labrafil® M 1969 CS (Gattefosse) (4)); PEG-6hydrogenated palm kernel oil (Labrafil® M 2130 BS (Gattefosse) (4));PEG-6 palm kernel oil (Labrafil® M 2130 CS (Gattefosse) (4)); PEG-6triolein (Labrafil® M 2735 CS (Gattefosse) (4)); PEG-8 corn oil(Labrafil® WL 2609 BS (Gattefosse) (6-7)); PEG-20 corn glycerides(Crovol M40 (Croda) (10)); PEG-20 almond glycerides (Crovol A40 (Croda)(10)); PEG-25 trioleate (TAGAT® TO (Goldschmidt) (11)); PEG-40 palmkernel oil (Crovol PK-70 (>10)); PEG-60 corn glycerides (Crovol M70(Croda) (15)); PEG-60 almond glycerides (Crovol A70 (Croda) (15)); PEG-4caprylic/capric triglyceride (Labrafac® Hydro (Gattefosse), (4-5));PEG-8 caprylic/capric glycerides (Labrasol (Gattefosse), Labrafac CM 10(Gattefosse) (>10)); PEG-6 caprylic/capric glycerides (SOFTIGEN® 767(Huls), Glycerox 767 (Croda) (19)); Lauroyl macrogol-32 glyceride(GELUCIRE 44/14 (Gattefosse) (14)); Stearoyl macrogol glyceride(GELUCIRE 50/13 (Gattefosse) (13)); Mono, di, tri, tetra esters ofvegetable oils and sorbitol (SorbitoGlyceride (Gattefosse) (<10));Pentaerythrityl tetraisostearate (Crodamol PTIS (Croda) (<10));Pentaerythrityl distearate (Albunol DS (Taiwan Surf.) (<10));Pentaerythrityl tetraoleate (Liponate PO-4 (Lipo Chem.) (<10));Pentaerythrityl tetrastearate (Liponate PS-4 (Lipo Chem.) (<10));Pentaerythrityl tetracaprylate/tetracaprate (Liponate PE-810 (LipoChem.), Crodamol PTC (Croda) (<10)); Pentaerythrityl tetraoctanoate(Nikkol Pentarate 408 (Nikko))); and combinations thereof.

Polyglycolized Fatty Acids: (listed as compound name (common commercialproduct name (supplier) (HLB)): Polyglyceryl-2 stearate (Nikkol DGMS(Nikko) (5-7)); Polyglyceryl-2 oleate (Nikkol DGMO (Nikko) (5-7));Polyglyceryl-2 isostearate (Nikkol DGMIS (Nikko) (5-7)); Polyglyceryl-3oleate (Caprol® 3GO (ABITEC), Drewpol 3-1-O (Stepan) (6.5));Polyglyceryl-4 oleate (Nikkol Tetraglyn 1-O (Nikko) (5-7));Polyglyceryl-4 stearate (Nikkol Tetraglyn 1-S(Nikko) (5-6));Polyglyceryl-6 oleate (Drewpol 6-1-O (Stepan), Nikkol Hexaglyn 1-O(Nikko) (9)); Polyglyceryl-10 laurate (Nikkol Decaglyn 1-L (Nikko)(15)); Polyglyceryl-10 oleate (Nikkol Decaglyn 1-O (Nikko) (14));Polyglyceryl-10 stearate (Nikkol Decaglyn 1-S (Nikko) (12));Polyglyceryl-6 ricinoleate (Nikkol Hexaglyn PR-15 (Nikko) (>8));Polyglyceryl-10 linoleate (Nikkol Decaglyn 1-LN (Nikko) (12));Polyglyceryl-6 pentaoleate (Nikkol Hexaglyn 5-O(Nikko) (<10));Polyglyceryl-3 dioleate (Cremophor GO32 (BASF) (<10)); Polyglyceryl-3distearate (Cremophor GS32 (BASF) (<10)); Polyglyceryl-4 pentaoleate(Nikkol Tetraglyn 5-O (Nikko) (<10)); Polyglyceryl-6 dioleate (Caprol®6G20 (ABITEC); Hodag PGO-62 (Calgene), PLUROL OLEIQUE CC 497(Gattefosse) (8.5)); Polyglyceryl-2 dioleate (Nikkol DGDO (Nikko) (7));Polyglyceryl-10 trioleate (Nikkol Decaglyn 3-O (Nikko) (7));Polyglyceryl-10 pentaoleate (Nikkol Decaglyn 5-O(Nikko) (3.5));Polyglyceryl-10 septaoleate (Nikkol Decaglyn 7-O (Nikko) (3));Polyglyceryl-10 tetraoleate (Caprol® 10G4O (ABITEC); Hodag PGO-62(CALGENE), Drewpol 10-4-O (Stepan) (6.2)); Polyglyceryl-10decaisostearate (Nikkol Decaglyn 10-IS (Nikko) (<10)); Polyglyceryl-101decaoleate (Drewpol 10-10-O (Stepan), Caprol 10G10O (ABITEC), NikkolDecaglyn 10-O (3.5)); Polyglyceryl-10 mono, dioleate (Caprol® PGE 860(ABITEC) (11)); Polyglyceryl polyricinoleate (Polymuls (Henkel) (3-20));and combinations thereof.

Propylene Glycol Fatty Acid Esters: (listed as compound name (commoncommercial product name (supplier) (HLB)): Propylene glycolmonocaprylate (Capryol 90 (Gattefosse), Nikkol Sefsol 218 (Nikko)(<10)); Propylene glycol monolaurate (Lauroglycol 90 (Gattefosse),Lauroglycol FCC (Gattefosse) (<10)); Propylene glycol oleate (LutrolOP2000 (BASF) (<10)); Propylene glycol myristate (Mirpyl (<10));Propylene glycol monostearate (ADM PGME-03 (ADM), LIPO PGMS (LipoChem.), Aldo® PGHMS (Lonza) (3-4)); Propylene glycol hydroxy stearate(<10)); Propylene glycol ricinoleate (PROPYMULS (Henkel) (<10));Propylene glycol isostearate (<10)); Propylene glycol monooleate(Myverol P-O6 (Eastman) (<10)); Propylene glycol dicaprylate/dicaprate(Captex® 200 (ABITEC), Miglyol® 840 (Huls), Neobee® M-20 (Stepan) (>6));Propylene glycol dioctanoate (Captex® 800 (ABITEC) (>6)); Propyleneglycol caprylate/caprate (LABRAFAC PG (Gattefosse) (>6)); Propyleneglycol dilaurate (>6)); Propylene glycol distearate (Kessco® PGDS(Stepan) (>6)); Propylene glycol dicaprylate (Nikkol Sefsol 228 (Nikko)(>6)); Propylene glycol dicaprate (Nikkol PDD (Nikko) (>6)); andcombinations thereof.

Mixtures of Propylene Glycol Esters and Glycerol-Esters:(listed ascompound name (common commercial product name (supplier) (HLB)):Oleic(ATMOS 300, ARLACEL 186 (ICI) (3-4)); Stearic (ATMOS 150 (3-4)); andcombinations thereof.

Mono- and Diglycerides:(listed as compound name (common commercialproduct name (supplier) (HLB)): Monopalmitolein (C16:1) (Larodan)(<10)); Monoelaidin (C18:1) (Larodan) (<10)); Monocaproin (C6) (Larodan)(<10)); Monocaprylin (Larodan) (<10)); Monocaprin (Larodan) (<10));Monolaurin (Larodan) (<10)); Glyceryl monomyristate (C14) (Nikkol MGM(Nikko) (3-4)); Glyceryl monooleate (C18:1) (PECEOL (Gattefosse), HodagGMO-D, Nikkol MGO (Nikko) (3-4)); Glyceryl monooleate (RYLO series(Danisco), DIMODAN series (Danisco), EMULDAN (Danisco), ALDO® MO FG(Lonza), Kessco GMO (Stepan), MONOMULS® series (Henkel), TEGIN O,DREWMULSE GMO (Stepan), Atlas G-695 (ICI), GMOrphic 80 (Eastman), ADMDMG-40, 70, and 100 (ADM), Myverol (Eastman) (3-4)); Glycerolmonooleate/linoleate (OLICINE (Gattefosse) (3-4)); Glycerolmonolinoleate (Maisine (Gattefosse), MYVEROL 18-92, Myverol 18-06(Eastman) (3-4)); Glyceryl ricinoleate (Softigen® 701 (Huls), HODAGGMR-D (Calgene), ALDO® MR (Lonza) (6)); Glyceryl monolaurate (ALDO® MLD(Lonza), Hodag GML (Calgene) (6.8)); Glycerol monopalmitate (EmalexGMS-P (Nihon) (4)); Glycerol monostearate (Capmul® GMS (ABITEC),Myvaplex (Eastman), IMWITOR® 191 (Huls), CUTINA GMS, Aldo® MS (Lonza),Nikkol MGS series (Nikko) (5-9)); Glyceryl mono-,dioleate (Capmul® GMO-K(ABITEC) (<10)); Glyceryl palmitic/stearic (CUTINA MD-A, ESTAGEL-G18(<10)); Glyceryl acetate (Lamegin® EE (Grunau GmbH) (<10)); Glyceryllaurate (Imwitor® 312 (Huls), Monomuls® 90-45 (Grunau GmbH), Aldo® MLD(Lonza) (4)); Glyceryl citrate/lactate/oleate/linoleate (Imwitor® 375(Huls) (<10)); Glyceryl caprylate (Imwitor® 308 (Huls), Capmul® MCMC8(ABITEC) (5-6)); Glyceryl caprylate/caprate (Capmul® MCM (ABITEC)(5-6)); Caprylic acid mono, diglycerides (Imwitor® 988 (Huls) (5-6));Caprylic/capric glycerides (Imwitor® 742 (Huls) (<10)); Mono- anddiacetylated monoglycerides (Myvacet® 9-45, Myvacet® 9-40, Myvacet® 9-08(Eastman), Lamegin® (Grunau) (3.8-4)); Glyceryl monostearate (Aldo® MS,Arlacel 129 (ICI), LIPO GMS (Lipo Chem.), Imwitor® 191 (Huls), Myvaplex(Eastman) (4.4)); Lactic acid esters of mono,diglycerides (LAMEGIN GLP(Henkel) (<10)); Dicaproin (C6) (Larodan) (<10); Dicaprin (C10)(Larodan) (<10); Dioctanoin (C8) (Larodan) (<10); Dimyristin (C14)(Larodan) (<10); Dipalmitin (C16) (Larodan) (<10); Distearin (Larodan)(<10); Glyceryl dilaurate (C12) (Capmul® GDL (ABITEC) (3-4)); Glyceryldioleate (Capmul® GDO (ABITEC) (3-4)); Glycerol esters of fatty acids(GELUCIRE 39/01 (Gattefosse), GELUCIRE 43/01 (Gattefosse) GELUCIRE 37/06(Gattefosse) (1 6)); Dipalmitolein (C16:1) (Larodan) (<10); 1,2 and1,3-diolein (C18:1) (Larodan) (<10); Dielaidin (C18:1) (Larodan) (<10);Dilinolein (C18:2) (Larodan) (<10); and combinations thereof.

Sterol and Sterol Derivatives: (listed as compound name (commoncommercial product name (supplier) (HLB)): Cholesterol, sitosterol,lanosterol (<10)); PEG-24 cholesterol ether (Solulan C-24 (Amerchol)(>10)); PEG-30 cholestanol (Nikkol DHC (Nikko) (>10)); Phytosterol(GENEROL series (Henkel) (<10)); PEG-25 phyto sterol (Nikkol BPSH-25(Nikko) (>10)); PEG-5 soya sterol (Nikkol BPS-5 (Nikko) (<10)); PEG-10soya sterol (Nikkol BPS-10 (Nikko) (<10)); PEG-20 soya sterol (NikkolBPS-20 (Nikko) (<10)); PEG-30 soya sterol (Nikkol BPS-30 (Nikko) (>10));and combinations thereof.

Polyethylene Glycol Sorbitan Fatty Acid Esters: (listed as compound name(common commercial product name (supplier) (HLB)): PEG-10 sorbitanlaurate (Liposorb L-10 (Lipo Chem.) (>10)); PEG-20 sorbitan monolaurate(Tween-20 (Atlas/ICI), Crillet 1 (Croda), DACOL MLS 20 (Condea) (17));PEG-4 sorbitan monolaurate (Tween-21 (Atlas/ICI), Crillet 11 (Croda)(13)); PEG-80 sorbitan monolaurate (Hodag PSML-80 (Calgene); T-Maz 28(>10)); PEG-6 sorbitan monolaurate (Nikkol GL-1 (Nikko) (16)); PEG-20sorbitan monopalmitate (Tween-40 (Atlas/ICI), Crillet 2 (Croda) (16));PEG-20 sorbitan monostearate (Tween-60 (Atlas/ICI), Crillet 3 (Croda)(15)); PEG-4 sorbitan monostearate (Tween-61 (Atlas/ICI), Crillet 31(Croda) (9.6)); PEG-8 sorbitan monostearate (DACOL MSS (Condea) (>10));PEG-6 sorbitan monostearate (Nikkol TS106 (Nikko) (11)); PEG-20 sorbitantristearate (Tween-65 (Atlas/ICI), Crillet 35 (Croda) (11)); PEG-6sorbitan tetrastearate (Nikkol GS-6 (Nikko) (3)); PEG-60 sorbitantetrastearate (Nikkol GS-460 (Nikko) (13)); PEG-5 sorbitan monooleate(Tween-81 (Atlas/ICI), Crillet 41 (Croda) (10)); PEG-6 sorbitanmonooleate (Nikkol TO-106 (Nikko) (10)); PEG-20 sorbitan monooleate(Tween-80 (Atlas/ICI), Crillet 4 (Croda) (15)); PEG-40 sorbitan oleate(Emalex ET 8040 (Nihon Emulsion) (18)); PBG-20 sorbitan trioleate(Tween-85 (Atlas/ICI), Crillet 45 (Croda) (11)); PEG-6 sorbitantetraoleate (Nikkol GO-4 (Nikko) (8.5)); PEG-30 sorbitan tetraoleate(Nikkol GO-430 (Nikko) (12)); PEG-40 sorbitan tetraoleate (Nikkol GO-440(Nikko) (13)); PEG-20 sorbitan monoisostearate (Tween-120 (Atlas/ICI),Crillet 6 (Croda) (>10)); PEG sorbitol hexaoleate (Atlas G-1086 (ICI)(10)); PEG-6 sorbitol hexastearate (Nikkol GS-6 (Nikko) (3)); andcombinations thereof.

Polyethylene Glycol Alkyl Ethers: (listed as compound name (commoncommercial product name (supplier) (HLB)): PEG-2 oleyl ether,oleth-2(Brij 92/93 (Atlas/ICI) (4.9)); PEG-3 oleyl ether,oleth-3 (Volpo 3(Croda) (<10)); PEG-5 oleyl ether,oleth-5 (Volpo 5 (Croda) (<10));PEG-10 oleyl ether,oleth-10 (Volpo 10 (Croda), Brij 96/97 (Atlas/ICI)(12)); PEG-20 oleyl ether,oleth-20 (Volpo 20 (Croda), Brij 98/99(Atlas/ICI) (15)); PEG-4 lauryl ether, laureth-4 (Brij 30 (Atlas/ICI)(9.7)); PEG-9 lauryl ether (>10)); PEG-23 lauryl ether, laureth-23 (Brij35 (Atlas/ICI) (17)); PEG-2 cetyl ether (Brij 52 (ICI) (5.3)); PEG-10cetyl ether (Brij 56 (ICI) (13)); PEG-20 cetyl ether (BriJ 58 (ICI)(16)); PEG-2 stearyl ether (Brij 72 (ICI) (4.9)); PEG-10 stearyl ether(Brij 76 (ICI) (12)); PEG-20 stearyl ether (Brij 78 (ICI) (15)); PEG-100stearyl ether (Brij 700 (ICI) (>10)); and combinations thereof.

Sugar Esters: (listed as compound name (common commercial product name(supplier) (HLB)): Sucrose distearate (SUCRO ESTER 7 (Gattefosse),Crodesta F-10 (Croda) (3)); Sucrose distearate/monostearate (SUCRO ESTER11 (Gattefosse), Crodesta F-110 (Croda) (12)); Sucrose dipalmitate(7.4)); Sucrose monostearate (Crodesta F-160 (Croda) (15)); Sucrosemonopalmitate (SUCRO ESTER 15 (Gattefosse) (>10)); Sucrose monolaurate(Saccharose monolaurate 1695 (Mitsubishi-Kasei) (15)); and combinationsthereof.

Polyethylene Glycol Alkyl Phenols: (listed as compound name (commoncommercial product name (supplier) (HLB)): PEG-10-100 nonyl phenol(Triton X series (Rohm & Haas), Igepal CA series (GAF, USA), Antarox CAseries (>10)); (GAF, UK); PEG-15-100 octyl phenol ether (Triton N-series(Rohm & Haas), Igepal CO series (GAF, USA), Antarox CO series (GAF, UK)(>10)); and combinations thereof.

Polyethylene-Polyoxypropylene Block Copolymers (AKA—“poloxamer”): Thesepolymers have the formula: HO(C<2>H<4>O)<a>(C<3>H<6>O)<b>(C<2>H<4>O)<a>Hwhere “a” and “b” denote the number of polyoxyethylene andpolyoxypropylene units, respectively. The compounds are listed bygeneric name, with the corresponding “a” and “b” values. POE-POP BlockCopolymers)); (a, b values in)); (HO(C<2>H<4>O)<a>)); (COMPOUND(C<3>H<6>O)<b>(C<2>H<4>O)<a>H (HLB)); (Poloxamer 105 (a=11 (b=16 (8));(Poloxamer 108 (a=46 (b=16 (>10)); (Poloxamer 122 (a=5 (b=21 (3));(Poloxamer 123 (a=7 (b=21 (7)); (Poloxamer 124 (a=11 (b=21 (>7));(Poloxamer 181 (a=3 (b=30)); (Poloxamer 182 (a=8 (b=30 (2)); (Poloxamer183 (a=10 (b=30)); (Poloxamer 184 (a=13 (b=30)); (Poloxamer 185 (a=19(b=30)); (Poloxamer 188 (a=75 (b=30 (29)); (Poloxamer 212 (a=8 (b=35));(Poloxamer 215 (a=24 (b=35)); (Poloxamer 217 (a=52 (b=35)); (Poloxamer231 (a=16 (b=39)); (Poloxamer 234 (a=22 (b=39)); (Poloxamer 235 (a=27(b=39)); (Poloxamer 237 (a=62 (b=39 (24)); (Poloxamer 238 (a=97 (b=39));(Poloxamer 282 (a=10 (b=47)); (Poloxamer 284 (a=21 (b=47)); (Poloxamer288 (a=122 (b=47 (>10)); (Poloxamer 331 (a=7 (b=54 (0.5)); (Poloxamer333 (a=20 (b=54)); (Poloxamer 334 (a=31 (b=54)); (Poloxamer 335 (a=38(b=54)); (Poloxamer 338 (a=128 (b=54)); (Poloxamer 401 (a=6 (b=67));(Poloxamer 402 (a=13 (b=67)); (Poloxamer 403 (a=21 (b=67)); (Poloxamer407 (a=98 (b=67)); and combinations thereof.

Sorbitan Fatty Acid Esters: (listed as compound name (common commercialproduct name (supplier) (HLB)): Sorbitan monolaurate (Span-20(Atlas/ICI), Crill 1 (Croda), Arlacel 20 (ICI) (8.6)); Sorbitanmonopalmitate (Span-40 (Atlas/ICI), Crill 2 (Croda), Nikkol SP-10(Nikko) (6.7)); Sorbitan monooleate (Span-80 (Atlas/ICI), Crill 4(Croda), Crill 50 (Croda) (4.3)); Sorbitan monostearate (Span-60(Atlas/ICI), Crill 3 (Croda), Nikkol SS-10 (Nikko) (4.7)); Sorbitantrioleate (Span-85 (Atlas/ICI), Crill 45 (Croda), Nikkol SO-30 (Nikko)(4.3)); Sorbitan sesquioleate (Arlacel-C (ICI), Crill 43 (Croda), NikkolSO-15 (Nikko) (3.7)); Sorbitan tristearate (Span-65 (Atlas/ICI) Crill 35(Croda), Nikkol SS-30 (Nikko) (2.1)); Sorbitan monoisostearate (Crill 6(Croda), Nikkol SI-10 (Nikko) (4.7)); Sorbitan sesquistearate (NikkolSS-15 (Nikko) (4.2)); and combinations thereof.

Lower Alcohol Fatty Acid Esters: (listed as compound name (commoncommercial product name (supplier) (HLB)): Ethyl oleate ((Crodamol EO(Croda), Nikkol EOO (Nikko) (<10)); Isopropyl myristate (Crodamol IPM(Croda) (<10)); Isopropyl palmitate (Crodamol IPP (Croda) (<10)); Ethyllinoleate (Nikkol VF-E (Nikko) (<10)); Isopropyl linoleate (Nikkol VF-IP(Nikko) (<10)); and combinations thereof.

Ionic Surfactants: (listed as compound name (HLB) Fatty acid salts(>10)); Sodium caproate; Sodium caprylate; Sodium caprate; Sodiumlaurate; Sodium myristate)); Sodium myristoleate; Sodium palmitate;Sodium palmitoleate; Sodium oleate (18); Sodium ricinoleate)); Sodiumlinoleate; Sodium linolenate; Sodium stearate; Sodium lauryl sulfate(40); Sodium tetradecyl sulfate; Sodium lauryl sarcosinate; Sodiumdioctyl sulfosuccinate; Bile Salts (>10); Sodium cholate; Sodiumtaurocholate; Sodium glycocholate; Sodium deoxycholate; Sodiumtaurodeoxycholate; Sodium glycodeoxycholate; Sodium ursodeoxycholate;Sodium chenodeoxycholate; Sodium taurochenodeoxycholate; Sodium glycocheno deoxycholate; Sodium cholylsarcosinate; Sodium N-methyltaurocholate; and combinations thereof.

Phospholipids: such as Egg/Soy lecithin (Epikuron™; Ovothin™); Lysoegg/soy lecithin; Hydroxylated lecithin; Lysophosphatidylcholine;Cardiolipin; Sphingomyelin; Phosphatidylcholine; Phosphatidylethanolamine; Phosphatidic acid; Phosphatidyl glycerol; Phosphatidylserine, and combinations thereof.

Phosphoric Acid Esters: Diethanolammonium polyoxyethylene-10 oleyl etherphosphate; Esterification products of fatty alcohols or fatty alcoholethoxylates with phosphoric acid or anhydride.

Carboxylates, such as: Ether carboxylates (by oxidation of terminal OHgroup of fatty alcohol ethoxylates) Succinylated monoglycerides; Sodiumstearyl fumarate; Stearoyl propylene glycol hydrogen succinate;Mono/diacetylated tartaric acid esters of mono- and diglycerides; Citricacid esters of mono-, diglycerides; Glyceryl-lacto esters of fattyacids; and combinations thereof.

Acyl lactylates such as: lactylic esters of fatty acids; calcium/sodiumstearoyl-2-lactylate; calcium/sodium stearoyl lactylate; alginate saltslike sodium alginate, calcium alginate and others; and combinationsthereof.

Hydrophilic Polymers such as: carboxyvinyl polymer,polyvinylpyrrolidone, polyvinyl alcohol, methacrylic acid copolymers,macrogol, starch, gelatin, dextrin, pullulan, agar, acacia,poly(ethylene glycol), poly(ethylene oxide), poly(vinyl alcohol),poly(ethylene-co-vinyl alcohol), poly(acrylic acid),poly(ethylene-co-acrylic acid), poly(ethyloxazoline), poly(vinylpyrrolidone), poly(ethylene-co-vinyl pyrrolidone), poly(maleic acid),poly(ethylene-co-maleic acid), poly(acrylamide), or poly(ethyleneoxide)-co-poly(propylene oxide); block copolymers, graft copolymers oflactic acid, glycolic acid, epsilon-caprolactone, lactic-co-glycolicacid oligomers, trimethylene carbonate, anhydrides, and amino acidsacrylates, benzoquinones, naphthoquinones and the like;N-vinylpyrrolidone-co-vinyl alcohol, poly(ethylene-co-vinyl alcohol);acrylic or methacrylic acid copolymers; carbomers, Chitosan,methacrylates (Eudragits), and combinations thereof.

Acids such as: acetic acid, hydrochloric acid, hydrobromic acid,hydriodic acid, phosphoric acid, sulfuric acid, nitric acid, acrylicacid, adipic acid, alginic acid, alkanesulfonic acid, an amino acid,ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid,citric acid, fatty acid, formic acid, fumaric acid, gluconic acid,hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid,methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid,propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid,succinic acid, tannic acid, tartaric acid, thioglycolic acid,toluenesulfonic acid, uric acid, salts thereof, and mixtures thereof.

Bases such as: amino acids, amino acid esters, ammonium hydroxide,potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate,aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesiumaluminum silicate, synthetic aluminum silicate, synthetic hydrotalcite,magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine,ethylenediamine, triethanolamine, triethylamine, triisopropanolamine,and mixtures of combinations thereof.

Chelating Agents such as: Sodium EDTA, Dieditate Sodium, and mixtures orcombinations thereof. Complexing Agents such as: HydroxypropylCyclodextrin, Hydroxy propyl beta Cyclodextrin, sulfabutyl ethercyclodextrin, and mixtures and combinations thereof. Salts such as:salts of acids, bases, salts of fatty acids, fatty acid glycerides,Salts of bile acids, and mixtures and combinations thereof.

Amides such as: for example 2-pyrrolidone, 2-piperidone,.epsilon.-caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone,N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide,polyvinylpyrrolidone and the like.

Alcohols such as: ethanol, isopropanol, butanol, benzyl alcohol,ethylene glycol, propylene glycol, glycerol, sorbitol, mannitol,dimethyl isosorbide, polyethylene glycol, fatty acid alcohol, vinylalcohol polypropylene glycol, polyvinylalcohol, tocopherols, cellulosecyclodextrins, other derivatives, forms, mixtures thereof, or the like.

Glycerols and Propylene Glycols such as: glycerine, propylene glycol,polypropylene glycol, polypropylene oxides, and mixtures thereof.Polyethylene Glycol (PEG) such as: PEG 300, PEG 400, PEG 4000, PEG 6000,PEG 8000, PEG 20000, and combinations thereof.

Esters such as: ethyl propionate, tributylcitrate, acetyltriethylcitrate, acetyl tributyl citrate, triethylcitrate, ethyl oleate,ethyl caprylate, ethyl butyrate, triacetin, propylene glycolmonoacetate, propylene glycol diacetate, epsilon-caprolactone andisomers thereof, .delta.-valerolactone and isomers thereof,beta-butyrolactone and isomers thereof dimethyl acetamide, dimethylisosorbide, N-methyl pyrrolidones, monooctanoin, diethylene glycolmonoethyl ether, or the like.

Bile acids such as: cholate, taurocholate, glycocholate, deoxycholate,taurodeoxycholate, chenodeoxycholate, glycodeoxycholate,glycochenodeoxycholate, taurochenodeoxycholate, ursodeoxycholate,lithocholate, tauroursodeoxycholate, glycoursodeoxycholate,cholylsarcosine)

Celluloses such as: microcrystalline cellulose, ethyl cellulose (EC),methylethyl cellulose (MEC), carboxymethyl cellulose (CMC),carboxymethyl ethylcellulose (CMEC), hydroxyethyl cellulose (HEC),hydroxypropyl cellulose (HPC), cellulose acetate (CA), cellulosepropionate (CPr), cellulose butyrate (CB), cellulose acetate butyrate(CAB), cellulose acetate phthalate (CAP), cellulose acetate trimellitate(CAT), hydroxypropyl methyl cellulose (HPMC), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methyl cellulose acetatesuccinate (HPMCAS), hydroxypropyl methyl cellulose acetate trimellitate(HPMCAT), and ethylhydroxy ethylcellulose (EHEC), various grades of lowviscosity (MW less than or equal to 50,000 daltons) and high viscosity(MW greater than 50,000 daltons) HPMC, and combinations thereof.

Cellulose Esters such as: Cellulose acetate, Cellulose Acetate Butyrate,Cellulose acetate phthalate, Hydroxypropyl methylcellulose phthalate,and combinations thereof.

Mucoadhesive Polymers such as for example tocopherols such as forexample tocopherol, tocopherol acetate, tocopherol succinate, andcombinations thereof.

Amino Acids and Modified Amino acids such as: aminoboronic acidderivatives, n-acetylcysteine, and mixtures thereof.

Sugars such as: maltose, sucrose, dextrose, lactose, fructose, mannitol,sucralose, fructalose, trehelose, dextrose, maltodextrose, andcombinations thereof.

Sugar Alcohols such as: mannitol, xylitol, sorbitol, combinationsthereof, and the like

Osmotic agents such as: Hydrophilic vinyl and acrylic polymers,polysaccharides such as calcium alginate, polyethylene oxide (PEO),polyethylene glycol (PEG), polypropylene glycol (PPG),poly(2-hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic)acid, polyvinylpyrrolidone (PVP) and crosslinked PVP, polyvinyl alcohol(PVA), PVA/PVP copolymers and PVA/PVP copolymers with hydrophobicmonomers such as methyl methacrylate, vinyl acetate, and the like,hydrophilic polyurethanes containing large PEO blocks, sodiumcroscarmellose, carrageenan, hydroxyethyl cellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropyl methyl cellulose (HPMC), carboxymethylcellulose (CMC) and carbox cellulose (CEC), sodium alginate,polycarbophil, gelatin, xanthan gum, and sodium starch glycolate and thelike.

Other carriers such as: dibasic calcium phosphate, croscarmellosesodium, sodium starch glycolate, sodium alginate, phospholipids,lecithins, proteins (e.g., collagen, gelatin, Zein, gluten, musselprotein, lipoprotein); carbohydrates (e.g., alginates, carrageenan,cellulose derivatives, pectin, starch); gums (e.g., xanthan gum, gumArabic, gum tragacanth, gum acacia); spermaceti; natural or syntheticwaxes; carnuaba wax; fatty acids (e.g., stearic acid, hydroxystearicacid); Magnesium stearate, calcium stearate, titanium dioxide,polyacrylic acid, silicates, magnesium aluminum silicates, siloxanes,mimeticones, paraffins, fatty alcohols; dibutyl phthalate; dibutylsebacate; diethyl phthalate; dimethyl phthalate; triethyl citrate; butyland glycol esters of fatty acids; mineral oil; cetyl alcohol; stearylalcohol; camphor oil; triethyl citrate, shellacs, benzalkonium chloride,methyl paraben, propyl paraben, sodium benzoate and the like.

In one embodiment, the pharmaceutical composition or oral dosage formcan be formulated to include at least one of the following preferredcarriers: citric acid, maleic acid, tartaric acid, ascorbic acid, lacticacid, and salts thereof, potassium hydroxide, sodium hydroxide, sodiumhydrogen carbonate, calcium carbonate, silicon dioxide, magnesiumaluminum silicate, triethylamine, fatty acid glycerides, pyrrolidone,polyvinylpyrrolidone, ethyl alcohol, benzyl alcohol, glycerol, propyleneglycol, polyethylene glycol, triethylcitrate, triacetin, benzylbenzoate, bile acid, salts of bile acid, ethyl cellulose, hydroxypropylethyl cellulose, cellulose esters, carbomer, methacrylates, polyvinylalcohol, gelatin, distearin, monopalmitolein tocopherol, tocopherolsuccinate, corn oil, olive oil, peanut oil, safflower oil, sesame oil,soybean oil, hydrogenated castor oil, glyceryl tricaprate, glyceryltrilinoleate, glyceryl tricaprylate/caprate, glyceryltricaprylate/caprate/linoleate, saturated polyglycolized glycerides,linoleic glycerides, caprylic/capric glycerides, capric acid, caprylicacid, palmitic acid, Lauric acid, stearic acid, linoleic acid, oleicacid, arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid,glyceryl monooleate, glyceryl monolinoleate, glyceryl monolaurate,glycerol monostearate, glyceryl distearate, glyceryl palmitostearate,glyceryl laurate, glyceryl caprylate, PEG-6 corn oil, PEG-6 apricotkernel oil, stearoyl macrogol glyceride, PEG-20 sorbitan monostearate,PEG-40 hydrogenated castor oil, PEG-35 castor oil, sodium oleate, sodiumlauryl sulfate, sodium lauryl sarcosinate, sodium dioctylsulfosuccinate, polyglyceryl-3 oleate, polyglyceryl-10 oleate,polyglyceryl-6 dioleate, polyglyceryl-10 mono, dioleate, poloxamer 188,poloxamer 108, poloxamer 182, propylene glycol monocaprylate, propyleneglycol monolaurate, propylene glycol dicaprylate/dicaprate, propyleneglycol caprylate/caprate, sorbitan monolaurate, sorbitan monopalmitate,sorbitan monooleate, sorbitan monostearate, sorbitan sesquioleate,sorbitan sesquistearate, maltose, sucrose, fructose, mannitol, xylitol,and combinations thereof.

In one embodiment, the pharmaceutical compositions or oral dosage formsof the present invention can be formulated to include a hydrophilicadditive. In another embodiment, the hydrophilic additive can be ahydrophilic surfactant. In one embodiment, when the hydrophilic additiveincludes a hydrophilic surfactants, the hydrophilic surfactant does notappreciably solubilize the ester of 17-hydroxyprogesterone. Non-limitingexamples of hydrophilic additives include salts of citric acid, maleicacid, tartaric acid, acetic acid, ascorbic acid, benzoic acid and lacticacid, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate,calcium carbonate, silicon dioxide, magnesium aluminum silicate,hydroxypropyl cyclodextrin, fatty acid glycerides, salts of bile acids,pyrrolidone, polyvinylpyrrolidone, ethyl alcohol, benzyl alcohol,glycerol, propylene glycol, polyethylene glycol methyl cellulose,hydroxypropyl methyl cellulose, cellulose ssters, carbomer, chitosan,methacrylates, polyvinyl alcohol, gelatin, PEG-8 caprylic/capricglycerides, lauroyl macrogol-32 glyceride, stearoyl macrogol glyceride,PEG-40 hydrogenated castor oil, PEG-35 castor oil, sodium oleate, sodiumlauryl sulfate, sodium lauryl sarcosinate, sodium dioctylsulfosuccinate, PEG-10 laurate, PEG-20 oleate, PEG-30 stearate, PEG-40laurate, PEG-20 glyceryl laurate, PEG-20 glyceryl tearate, PEG-40glyceryl laurate, PEG-20 glyceryl oleate, PEG-10 sorbitan laurate,PEG-20 sorbitan monolaurate, PEG-20 sorbitan monooleate, polyglyceryl-10oleate, polyglyceryl-10 mono, dioleate, poloxamer 188, poloxamer 108,maltose, sucrose, fructose, mannitol, xylitol, and combinations thereof.

In another particular embodiment, the carrier can be a hydrophilicsurfactant and can be ionic or non-ionic surfactant. Non-limitingexamples of hydrophilic surfactants include proteins, gelatin, salts ofbile acids, PEG-8 caprylic/capric glycerides, lauroyl macrogol-32glyceride, stearoyl macrogol glyceride, PEG-40 hydrogenated castor oil,PEG-35 castor oil, sodium oleate, sodium lauryl sulfate, sodium laurylsarcosinate, sodium dioctyl sulfosuccinate, PEG-10 laurate, PEG-20oleate, PEG-30 stearate, PEG-40 laurate, PEG-20 glyceryl laurate, PEG-20glyceryl tearate, PEG-40 glyceryl laurate, PEG-20 glyceryl oleate,PEG-10 sorbitan laurate, PEG-20 sorbitan monolaurate, PEG-20 sorbitanmonooleate, polyglyceryl-10 oleate, polyglyceryl-10 mono, dioleate,poloxamer 188, poloxamer 108, and combinations thereof.

In one embodiment, the hydrophilic additive can be free of hydrophilicsurfactants, and can be citric acid, maleic acid, tartaric acid, aceticacid, ascorbic acid, benzoic acid, lactic acid, potassium hydroxide,sodium hydroxide, sodium hydrogen carbonate, calcium carbonate, silicondioxide, magnesium aluminum silicate, hydroxypropyl cyclodextrin,pyrrolidone, polyvinylpyrrolidone, ethyl alcohol, benzyl alcohol,glycerol, propylene glycol, polyethylene glycol, methyl cellulose,hydroxypropyl methyl cellulose, cellulose esters, carbomer, chitosan,methacrylates, polyvinyl alcohol, gelatin, maltose, sucrose, fructose,mannitol, xylitol, and combinations thereof.

In another embodiment, the carrier of the pharmaceutical compositions ororal dosage forms can include a lipophilic additive. Non-limitingexamples of lipophilic additives include tributylcitrate,triethylcitrate, triacetin, ethyl cellulose, cellulose esters, celluloseacetate, cellulose acetates butyrate, cellulose acetate phthalate,hydroxypropyl methylcellulose phthalate, tocopherol, tocopherol acetate,tocopherol succinate, corn oil, olive oil, peanut oil, safflower oil,sesame oil, soybean oil, hydrogenated castor oil, glyceryl tricaprate,glyceryl trilaurate, glyceryl trioleate, glyceryl trilinoleate, glyceryltricaprylate/caprate, glyceryl tricaprylate/caprate/laurate, glyceryltricaprylate/caprate/linoleate, glyceryl tricaprylate/caprate/stearate,saturated polyglycolized glycerides linoleic glycerides, caprylic/capricglycerides capric acid, caprylic acid, palmitic acid, lauric acid,stearic acid, linoleic acid, oleic acid, arachidonic acid,eicosapentaenoic acid, docosahexaenoic acid, glyceryl monooleate,glyceryl monolinoleate, glyceryl monolaurate, glycerol monostearate,glyceryl distearate, glyceryl palmitostearate, glyceryl laurate,glyceryl caprylate, distearin, monopalmitolein, monolaurin, ethyloleate, PEG-6 corn oil, PEG-6 apricot kernel oil, PEG-4 caprylic/caprictriglyceride, PEG-20 sorbitan monostearate, PEG-4 laurate, PEG-6dilaurate, polyglyceryl-3 oleate, polyglyceryl-6 dioleate, poloxamer182, propylene glycol monocaprylate, propylene glycol monolaurate,propylene glycol dicaprylate/dicaprate, propylene glycolcaprylate/caprate, sorbitan monolaurate, sorbitan monopalmitate,sorbitan monooleate, sorbitan monostearate, sorbitan sesquioleate,sorbitan sesquistearate, and combinations thereof. In one embodiment,the carrier of the current invention can include at least 50 wt % oflipophilic additive.

In a particular embodiment, the lipophilic additive is at least oneagent selected from tributylcitrate, triethylcitrate, triacetin, ethylcellulose, cellulose esters, cellulose acetate, cellulose acetatesbutyrate, cellulose acetate phthalate, hydroxypropyl methylcellulosephthalate, tocopherol, tocopherol acetate, tocopherol succinate,triglycerides, corn oil, olive oil, peanut oil, safflower oil, sesameoil, soybean oil, hydrogenated castor oil, glyceryl tricaprate, glyceryltrilaurate, glyceryl trioleate, glyceryl trilinoleate, glyceryltricaprylate/caprate, glyceryl tricaprylate/caprate/laurate, glyceryltricaprylate/caprate/linoleate, glyceryl tricaprylate/caprate/stearate,saturated polyglycolized glycerides linoleic glycerides, caprylic/capricglycerides, capric acid, caprylic acid, palmitic acid, lauric acid,stearic acid, linoleic acid, oleic acid, arachidonic acid,eicosapentaenoic acid, docosahexaenoic acid, glyceryl distearate,glyceryl palmitostearate, distearin, tristearin, paraffin oil, bess wax,animal fat, phytosterol, cholesterol, shellac and combinations thereof.

In a particular embodiment, the lipophilic additive is a triglyceride.Non-limiting examples of triglycerides suitable for this inventioninclude corn oil, olive oil, peanut oil, palm oil, coconut oil, arachisoil, safflower oil, sesame oil, soybean oil, castor oil, primrose oil,cotton seed oil, vegetable oil, borage oil, linseed oil, flax seed oil,omega oils, partially or fully hydrogenated castor oil, fish oil, sharkoil, whale oil, seal oil, glyceryl tricaprate, glyceryl trilaurate,glyceryl trioleate, glyceryl trilinoleate, glyceryltricaprylate/caprate, glyceryl tricaprylate/caprate/laurate, glyceryltricaprylate/caprate/linoleate, glyceryl tricaprylate/caprate/stearate,saturated polyglycolized glycerides linoleic glycerides, caprylic/capricglycerides, tristearin and the like, and combinations thereof

In one embodiment, the lipophilic additive can be free of lipophilicsurfactants. In one particular embodiment, the carrier is a lipophilicsurfactant. Non-limiting examples of lipophilic surfactants suitable forthis invention include tributylcitrate, triethylcitrate, triacetin,ethyl cellulose, cellulose esters, cellulose acetate, cellulose acetatesbutyrate, benzyl benzoate, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, tocopherol, tocopherol acetate, tocopherolsuccinate, corn oil, olive oil, peanut oil, safflower oil, sesame oil,soybean oil, hydrogenated castor oil, glyceryl tricaprate, glyceryltrilaurate, glyceryl trioleate, glyceryl trilinoleate, glyceryltricaprylate/caprate, glyceryl tricaprylate/caprate/laurate, glyceryltricaprylate/caprate/linoleate, glyceryl tricaprylate/caprate/stearate,saturated polyglycolized glycerides linoleic glycerides, caprylic/capricglycerides capric acid, caprylic acid, palmitic acid, lauric acid,stearic acid, linoleic acid, oleic acid, arachidonic acid,eicosapentaenoic acid, docosahexaenoic acid, glyceryl monooleate,glyceryl monolinoleate, glyceryl monolaurate, glycerol monostearate,glyceryl distearate, glyceryl palmitostearate, glyceryl laurate,glyceryl caprylate, distearin, monopalmitolein, monolaurin, ethyloleate, PEG-6 corn oil, PEG-6 apricot kernel oil, PEG-4 caprylic/caprictriglyceride, PEG-20 sorbitan monostearate, PEG-4 laurate, PEG-6dilaurate, polyglyceryl-3 oleate, polyglyceryl-6 dioleate, poloxamer182, propylene glycol monocaprylate, propylene glycol monolaurate,propylene glycol dicaprylate/dicaprate, propylene glycolcaprylate/caprate, sorbitan monolaurate, sorbitan monopalmitate,sorbitan monooleate, sorbitan monostearate, sorbitan sesquioleate,sorbitan sesquistearate, and combinations thereof.

In another particular embodiment, the compositions or dosage form of thepresent invention can be free of triglycerides, or substantially free oftriglycerides. Thus, in one embodiment, the present invention does notinclude lipophilic or hydrophilic additive which contain triglyceridesas an intended or added component. However, it should be appreciatedthat the present invention does not exclude the use of lipophilic orhydrophilic additives which contain small amounts of triglycerides asimpurities or as unreacted starting material. It is expected that whensuch lipophilic or hydrophilic additive is used in the compositions ofthe present invention, the total triglyceride content does not exceed 5%by weight of the composition or dosage form. Thus, “substantiallytriglyceride-free” should be understood as meaning free of addedtriglycerides, and the triglyceride impurity from the lipophilic orhydrophilic additives constitute about 5%, or less than 5%, less than2%, or preferably 0% (triglyceride free), by weight of the composition.Further, the present invention does not exclude lipophilic orhydrophilic additives that are derivatives of triglycerides, such as forexample polyethylene glycol or propylene glycol derivatives oftriglycerides; while these derivatized triglycerides may have surfactantproperties, the triglycerides are not surfactants by themselves.

Non-limiting examples of such lipophilic additives includetributylcitrate, triethylcitrate, triacetin, ethyl cellulose, celluloseesters, cellulose acetate, cellulose acetates butyrate, celluloseacetate phthalate, hydroxypropyl methylcellulose phthalate, tocopherol,tocopherol acetate, tocopherol succinate, saturated polyglycolizedglycerides linoleic glycerides, caprylic/capric glycerides capric acid,caprylic acid, palmitic acid, lauric acid, stearic acid, linoleic acid,oleic acid, arachidonic acid, eicosapentaenoic acid, benzyl benzoate,docosahexaenoic acid, glyceryl monooleate, glyceryl monolinoleate,glyceryl monolaurate, glycerol monostearate, glyceryl distearate,glyceryl palmitostearate, glyceryl laurate, glyceryl caprylate,distearin, monopalmitolein, monolaurin, ethyl oleate, PEG-6 corn oil,PEG-6 apricot kernel oil, PEG-4 caprylic/capric triglyceride, PEG-20sorbitan monostearate, PEG-4 laurate, PEG-6 dilaurate, polyglyceryl-3oleate, polyglyceryl-6 dioleate, poloxamer 182, propylene glycolmonocaprylate, propylene glycol monolaurate, propylene glycoldicaprylate/dicaprate, propylene glycol caprylate/caprate, sorbitanmonolaurate, sorbitan monopalmitate, sorbitan monooleate, sorbitanmonostearate, sorbitan sesquioleate, sorbitan sesquistearate, andcombinations thereof.

In some embodiments, the carrier of the current invention can be acontrol release agent. In a particular embodiment, the control releaseagent is selected from the group consisting of the said hydrophilicadditives or lipophilic additives or a mixture thereof. In anotherparticular embodiment, the compositions or dosage forms of the presentinvention can be free of lipophilic surfactant. In another particularembodiment, the compositions or dosage form of the present invention canbe free of lipophilic additive.

As discussed above, in some embodiments, the pharmaceutical compositionsand the oral dosage forms of the present disclosure can include at leastone hydrophilic additive and at least one lipophilic additive. In oneembodiment, when both a hydrophilic additive and a lipophilic additiveare present, they can be present at a lipophilic additive to hydrophilicadditive ratio of about 99:1 to about 1:99. In one embodiment, thelipophilic additive to hydrophilic additive ratio can be about 95:5 toabout 5:95. In another embodiment, the lipophilic additive tohydrophilic additive ratio can be about 90:10 to about 10:90. In oneembodiment, the lipophilic additive to hydrophilic additive ratio can beof about 90:10 to about 1:99. In another specific embodiment, thelipophilic additive to hydrophilic additive ratio can be of about 80:20to about 20:80. In another specific embodiment, the lipophilic additiveto hydrophilic additive ratio can be of about 70:30 to about 30:70. Inanother specific embodiment, the lipophilic additive to hydrophilicadditive ratio can be of about 60:40 to about 40:60. In another specificembodiment, the lipophilic additive to hydrophilic additive ratio can beabout 50:50.

In a separate embodiment, when both a hydrophilic surfactant and alipophilic additive are present, they can be present in amounts suchthat when 1 part by weight of the mixture of the hydrophilic surfactantand lipophilic additive is mixed 99 parts of an aqueous diluent, thedispersion so obtained so obtained can be colloidal, hazy or unclear.For example, the aqueous diluent used for dispersion is either water or0.5% w/v sodium lauryl sulfate in water. In a specific embodiment, thedispersion can exhibit an absorbance greater than 0.1 when determinedusing a spectrophotometer at 400 nm. In another specific embodiment, theabsorbance is greater than 0.3 at 400 nm. In another embodiment, themean particle size of the dispersion is about 60 nm or more. In anotherspecific embodiment, the mean particle size of the dispersion is about100 nm or more. In another specific embodiment, the mean particle sizeof the dispersion is about 150 nm or more. In yet another specificembodiment, the mean particle size of the dispersion is about 200 nm ormore. In yet another specific embodiment, the mean particle size of thedispersion is about 250 nm or more. For example, the aqueous diluentused for dispersion is either water or 0.5% w/v sodium lauryl sulfate inwater. For the purpose of this invention, the dispersion is deemed clearif it appears clear to the naked eye. In one embodiment, the dispersioncan be clear.

The carrier can be present in an amount sufficient to solubilize theester of 17 hydroxyprogesterone. In some aspects, the carrier of thepresent invention aids in solubilizing a significant amount of the esterof 17-hydroxyprogesterone in the composition. In one embodiment, thecarrier can solubilize 20 wt % or more of the amount of the ester of17-hydroxyprogesterone. In another embodiment, the carrier can aidloading of greater than about 10% w/w/of the ester in the compositionand/or dosage form. In another embodiment, the loading achieved by thecarrier can be greater than about 12% w/w of the composition and/ordosage form. In another embodiment, the loading achieved by the carriercan be greater than about 15% w/w of the composition and/or dosage form.In another embodiment, the loading attained by inclusion of the carriercan be greater than about 18% w/w of the composition and/or dosage form.In further embodiments, the loading attained by inclusion of the carriercan be greater than about 20%; greater than about 25%, greater thanabout 30%, greater than about 35%, greater than about 40%, greater thanabout 50%, greater than about 60%, greater than about 75%, or greaterthan about 90%, with each percentage based on w/w of the compositionand/or dosage form.

In one embodiment, the carrier can include benzyl alcohol, benzylbenzoate, mixtures thereof. In another embodiment, the carrier caninclude benzyl alcohol, benzyl benzoate, or mixtures thereof and theamount of the ester of 17-hydroxyprogesterone can be between about 5 toabout 80% w/w of the total composition. In one embodiment, when thecarrier includes benzyl alcohol, benzyl benzoate, or mixtures thereof,the amount of the ester of 17-hydroxyprogesterone can be between about 5to about 80% w/w of the total composition. In one embodiment, the amountof the ester of 17 hydroxyprogesterone can be between 5% to about 60%w/w of the total composition. In another specific embodiment, when thecarrier includes benzyl alcohol, benzyl benzoate, or mixtures thereof,the amount of the ester of 17-hydroxyprogesterone can be between about 5to about 40% w/w of the total composition. In another specificembodiment, when the carrier includes benzyl alcohol, benzyl benzoate,or mixtures thereof, the amount of the ester of 17-hydroxyprogesteronecan be between about 5 to about 30% w/w of the total composition. Inanother specific embodiment, when the carrier includes benzyl alcohol,benzyl benzoate, or mixtures thereof, the amount of the ester of17-hydroxyprogesterone can be between about 5 to about 25% w/w of thetotal composition. In one specific embodiment, when the carrier includesbenzyl alcohol, benzyl benzoate, or mixtures thereof, the ester of17-hydroxyprogesterone can be fully solubilized in the compositionand/or the dosage form. In another specific embodiment, the ester of17-hydroxyprogesterone can be partially solubilized in the dosage form.In another specific embodiment, the ester of 17-hydroxyprogesterone canbe 17-hydroxyprogesterone caproate.

In one embodiment the ratio of the amount of the ester of17-hydroxyprogesterone to the sum of the amounts of benzyl alcohol andbenzyl benzoate present in the composition or oral dosage form can beabout 1:0.01 (W/W) to about 1:5 (W/W). In another embodiment, the ratiocan be about 1:0.01 (W/W) to about 1:3.5 (W/W). In another embodiment,the ratio of the amount of the ester of 17-hydroxyprogesterone to thesum of the amounts of benzyl alcohol and benzyl benzoate present in thecomposition or oral dosage form can be about 1:0.01 (W/W) to about 1:2.5(W/W). In another embodiment, the ratio of the amount of the ester of17-hydroxyprogesterone to the sum of the amounts of benzyl alcohol andbenzyl benzoate present in the composition or oral dosage form can beabout 1:0.01 to about 1:2 (W/W).

The pharmaceutical compositions and oral dosage forms can be formulatedand delivered in a variety of solid or liquid dosage forms. Non-limitingexamples of such dosage forms include powder, granulate, particulate,bead, pellet, sprinkle, suspension, solution, tablet, capsule, andcombinations thereof. In one embodiment, the pharmaceutical compositionor oral dosage form can be in the form of a capsule. In anotherembodiment, the pharmaceutical composition or oral dosage form can be inthe form of a tablet. In one embodiment, the dosage form is a hard or asoft capsule. The capsule can be made of conventional capsule shellmaterials known in the art; such materials can include, but are notlimited to gelatins, celluloses, starches, methacrylates, carrageenans,polyvinyl alcohols, and the like. In another embodiment, the capsule isan immediate release dosage form. In yet another embodiment, the capsuleis a controlled release dosage form. In another embodiment, the tabletis an immediate release dosage form. In another embodiment, the tabletis a controlled release dosage form.

In one embodiment, the volume of the capsule can be about 1.5 mL orless. In another embodiment, the volume of capsule can be about 1.2 mLor less. In one particular embodiment, the volume of the capsule can beabout 0.8 mL or less. In another embodiment, the ratio of the weight offill material encapsulated within the capsule to the capsule volume canbe between about 0.3 g/mL to about 3.5 g/mL. In a particular embodiment,the ratio can be between 0.6 g/mL to about 2.5 g/mL. In anotherparticular embodiment, the ratio can be between 0.6 g/mL to about 1.2g/mL.

In another embodiment, the pharmaceutical capsule oral dosage form ofthe current invention can have a ratio of the amount of the ester of17-hydroxyprogesterone in the composition to the fill volume of thecapsule between about 0.02 g/mL to about 0.8 g/mL. In anotherembodiment, the ratio can be between about 0.02 g/mL to about 0.7 g/mL.In a specific embodiment, the ratio can be between about 0.02 g/mL toabout 0.5 g/mL. In another specific embodiment, the ratio can be betweenabout 0.05 g/mL to about 0.5 g/mL. In another specific embodiment, theratio can be between about 0.05 g/mL to about 0.35 g/mL. In anotherspecific embodiment, the ratio can be between about 0.05 g/mL to about0.3 g/mL. In another specific embodiment, the ratio can be between about0.1 g/mL to about 0.25 g/mL.

The oral dosage forms of the present invention can be formulated toinclude an amount of an ester of 17-hydroxyprogesterone equivalent toabout 10 mg to about 800 mg of 17-hydroxyprogesterone. In oneembodiment, the oral dosage form can be formulated to include an amountof ester of 17-hydroxyprogesterone equivalent to 20 mg to about 400 mgof 17-hydroxyprogesterone. The pharmaceutical composition and oraldosage forms of the present invention can be formulated to beadministered to a subject in order to provide a daily dose of the esterof 17-hydroxyprogesterone that is equivalent to about 40 mg to about3200 mg of 17-hydroxyprogesterone. In one embodiment, the oral dosageform can be a capsule and the capsule includes from about 10 mg to about300 mg 17-hydroxyprogesterone caproate. In another embodiment, the oraldosage form can be a tablet and the tablet includes from about 20 mg toabout 800 mg of 17-hydroxyprogesterone caproate.

In order to provide a desired daily dose, the pharmaceuticalcompositions and oral dosage forms can be formulated to be administeredat various dosing intervals. In one embodiment, the compositions or oraldosage forms can be formulated for administration about once every 8hours. In another embodiment, the compositions or oral dosage forms canbe formulated for administration to a subject, such as a human subject,once every 6 hours. In another embodiment, the compositions or oraldosage forms can be formulated for administration about once every 12hours. In yet a further embodiment, the compositions or oral dosageforms can be formulated for administration about once every 24 hours.

In one aspect, the oral dosage forms of the present invention can beused to treat pregnant female subjects who are at risk of preterm birth.The methods of treatment include the step of orally administering to thefemale subject the oral pharmaceutical composition. In anotherembodiment, the oral dosage forms can be administered to subjects inneed thereof. The administration of the oral dosage form can treat atleast one condition selected from preterm labor, preterm birth,infertility and miscarriage. In one embodiment, the subject receivingadministration of the pharmaceutical composition or oral dosage form canbe experiencing or be at risk of at least two of: singleton pregnancy,history of preterm labor and/or preterm birth, history of pretermdelivery, shortened cervix, and effaced cervix, history of more at leastone miscarriage, and history of multifetal gestation. The conditions andthe relative treatment can be based on their primary and secondaryoutcome measurements associated with the administration of the ester of17-hydroxyprogesterone.

In one embodiment, upon single administration to a human subject, thepharmaceutical compositions or oral dosage forms of the presentinvention comprising an ester of 17-hydroxyprogesterone can provide a17-hydroxyprogesterone equivalent C_(avg-24h) greater than about 0.7ng/mL. In another embodiment, the oral dosage form or the compositioncan provide a C_(avg-24h) of 17-hydroxyprogesterone equivalents greaterthan about 10 ng/mL. In another embodiment, the oral dosage form or thecomposition can provide a C_(avg-24h) of 17-hydroxyprogesteroneequivalents greater than about 30 ng/mL. In another embodiment, the oraldosage form or the composition can provide a C_(avg-24h) of17-hydroxyprogesterone equivalents greater than about 50 ng/mL. In yet afurther embodiment, the oral dosage form or the composition can providea C_(avg-24h) of 17-hydroxyprogesterone equivalents greater than about100 ng/mL. In one embodiment, the said 17-hydroxyprogesterone equivalentC_(avg-24h) is determined by an HPLC-MS/MS method of analysis of theplasma, serum or blood samples collected following the oraladministration.

In one embodiment, upon single administration to a human subject thepharmaceutical compositions or oral dosage forms of the presentinvention comprising 17-hydroxyprogesterone caproate, can provide a17-hydroxyprogesterone caproate C_(avg-24h) equal to about 1.0 ng/mL ormore. In another embodiment, the oral dosage form or the composition canprovide a 17-hydroxyprogesterone caproate C_(avg-24h) equal to about 20ng/mL or more. In another embodiment, the oral dosage form or thecomposition can provide a 17-hydroxyprogesterone caproate C_(avg-24h)equal to about 50 ng/mL or more. In another embodiment, the oral dosageform or the composition can provide a 17-hydroxyprogesterone caproateC_(avg-24h) equal to about 100 ng/mL or more. In one embodiment, thesaid 17-hydroxyprogesterone caproate C_(avg-24h) is determined by anHPLC-MS/MS method of analysis of the plasma, serum or blood samplescollected following the oral administration.

It was surprisingly found that the compositions and/or dosage forms ofthis invention provided significantly enhanced bioavailability of 17hydroxyprogesterone caproate as a function of the oral dose of the 17hydroxyprogesterone caproate administered to a subject. Accordingly, thecompositions or dosage forms of this invention provide, upon single doseoral administration, an AUC_((0-24h)) to dose ratio of about 10 or less,wherein the dose is the amount in mg of the 17-hydroxyprogesteronecaproate administered. In one embodiment, the ratio of the17-hydroxyprogesterone caproate AUC_((0-24h)) to dose of the17-hydroxyprogesterone caproate administered can be about 0.2 ng*h mL⁻¹mg⁻¹ to about 10 ng*h mL⁻¹ mg⁻¹. In another embodiment, the ratio of the17-hydroxyprogesterone caproate AUC_((0-24h)) to dose of the17-hydroxyprogesterone caproate administered can be about 0.3 ng*h mL⁻¹mg⁻¹ to about 7 ng*h mL⁻¹ mg⁻¹. In a specific embodiment, theAUC_((0-24h)) to dose ratio is between about 0.5 and about 6 ng*h mL⁻¹mg⁻¹.

In a specific embodiment, upon single administration of thepharmaceutical compositions or oral dosage forms containing17-hydroxyprogesterone caproate of the present invention to a humansubject under fed condition, the oral dosage form or pharmaceuticalcomposition can provide a 17-hydroxyprogesterone caproate C_(avg-24h) ofgreater than about 1.0 ng/mL. In another specific embodiment, thepharmaceutical compositions or oral dosage forms containing17-hydroxyprogesterone of the present invention can provide a steadystate 17-hydroxyprogesterone caproate C_(avg-24h) of greater than about1.0 ng/mL, when administered to a human subject under fed condition. Inone embodiment, the said C_(avg-24h) is determined by an HPLC-MS/MSmethod of analysis of the plasma, serum or blood samples collectedfollowing the administration. In another embodiment, the compositionsand oral dosage forms disclosed herein can be orally administered withfood or without regards to the food or food content. In a specificembodiment, the compositions and oral dosage forms containing caproateester of 17-hydroxyprogesterone as disclosed herein can be orallyadministered with food or without regards to the food or food content.

In one embodiment, the oral dosage form can be orally administered withfood or under fed condition. In another embodiment, the composition ororal dosage form can be administered with a normal or standard meal. Ina specific embodiment, the composition or oral dosage form can beadministered with a food or meal, such as a meal that provides about 200calories to about 1000 calories of energy. In another specificembodiment, the composition or oral dosage form can be administered witha meal that provides about 50% of the calories from the fat. In anotherembodiment, the composition or oral dosage form can be administered witha high-fat, high calorie meal. In another embodiment, the composition ororal dosage form can be administered with a standard meal that providesabout 500 calories to about 1000 calories of energy. The compositionalmake-up of the meals that are administered can vary depending on thetastes and dietary needs of a subject. However, in some situations itmay be beneficial to administer the compositions and oral dosage formswith meals that provide no fat to about 50 g of fat. In one embodiment,the meal can provide about 3 g to about 50 g of fat. In yet a furtherembodiment, the meal can provide 10 g to about 50 g of fat. In yetanother embodiment, the meal can provide about 15 g to about 35 g offat. In one embodiment, when the oral dosage form is administered to ahuman female, it can be done without regard to the presence of ornutritional make-up of a meal. In another embodiment, when administeringthe oral dosage form, the total daily dose of the ester of 17 HPadministered to human female subject with food or under fed condition isfrom about 20% to about 80% of the total daily dose administered withoutmeals, for a similar therapeutic benefit. In a specific embodiment, thedaily dose under fed condition is from about 20% to about 60% of thetotal daily dose administered without meals, for a similar therapeuticbenefit. In another embodiment, the composition or oral dosage form canbe administered without food or under fasted condition.

The oral bioavailability of the ester of 17-hydroxyprogesterone can beenhanced by using the said ester in the form of fine particulate, forexample milled, micronized or nanosized etc, in the composition and/orthe dosage form of the current invention. Further, the oralbioavailability can be enhanced by using the ester along with a carrierthat aids the release of at least 20% more of the ester from thecomposition or dosage form when exposed to an aqueous medium compared toan equivalent dose of the ester without the carrier of the currentinvention. In a specific embodiment the oral bioavailability of thecaproate ester of 17-hydroxyprogesterone can be enhanced by using thesaid ester in the form of fine particulate, for example milled,micronized or nanosized or combinations thereof in the compositionand/or the dosage form of the current invention.

Accordingly, in one embodiment, the oral bioavailability of the ester of17-hydroxyprogesterone is at least 10% more for the compositions or adosage forms of the current invention that releases at least 20% of theester in an aqueous medium compared to an equivalent dose of the esterpresent in an “untreated” particulate form such as for example asunmilled or unmicronized particulate forms. In another embodiment, theoral bioavailability of the ester of 17-hydroxyprogesterone is at least10% more for the compositions or a dosage forms of the current inventionthat releases at least 20% more of the ester from the composition ordosage form when exposed to an aqueous medium compared to an equivalentdose of the ester without the carrier of the current invention. In aspecific embodiment, the said ester is 17-hydroxyprogesterone caproate.

The ester of 17-hydroxyprogesterone can be a substrate to theP-glycoproteins (P-gp) the efflux transporter systems. Hence, in oneembodiment, the oral bioavailability can be enhanced by at least 10% byco-administering the ester of 17-hydroxyprogesterone of the currentinvention with an effective amount of P-gp and/or CYP3A4 inhibitingagents e.g., star fruit, grape fruit juice, bergamottin, cafestol (as inunfiltered coffee), ketoconazole, erythromycin, mibefradil, loperamideetc.

In a further aspect, the oral pharmaceutical compositions or the oraldosage forms of the ester of 17-hydroxyprogesterone according to thecurrent invention can be used for providing luteal support for a subjectin need thereof. In one embodiment, the oral composition or the oraldosage form can be formulated to enable modulation or titration of thedose and/or dosing regimen of the ester of 17-hydroxyprogesterone forproviding effective luteal support to a subject in need thereof. In oneparticular embodiment, the dose of the ester of 17-hydroxyprogesteronein the form of oral compositions or dosage forms of the presentinvention may be modulated or titrated to provide effective lutealsupport as needed at the during early pregnancy. In another particularembodiment, the dose of the ester of 17-hydroxyprogesterone in the formof oral compositions or dosage forms of the present invention may bemodulated or titrated to provide effective luteal support as neededbased on the body mass index (BMI) of the subject. In another particularembodiment, the dose of the ester of 17-hydroxyprogesterone in the formof oral compositions or dosage forms of the present invention may bemodulated or titrated to provide effective luteal support as neededbased on the race or ethnicity of the subject.

An example of the dose modulation or titration can be based on the totaldose per day, and can include administration of a higher initial loadingdose or bolus dose, followed by a lower effective standard dose.Similarly, the dose modulation or titration can be based on the totaldose per week and can include administration of a higher initial loadingdose or bolus dose in the initial days of the week followed by a lowereffective standard dose in the later days of the week. The dosingregimen can include ramping up of (i.e. progressive increments) thedaily dose in accordance with the progression of pregnancy. In aspecific embodiment the ester is 17-hydroxyprogesterone caproate(17-hydroxyprogesterone caproate).

In another embodiment, the daily oral dose administered with food of17-hydroxyprogesterone caproate is from about 40 mg to about 5000 mg. Inanother embodiment, the daily oral dose is from about 40 mg to about4000 mg. In another embodiment, the daily oral dose is from about 80 mgto about 4000 mg. In another embodiment, the daily oral dose is fromabout 150 mg to about 4000 mg. In another embodiment, the daily oraldose is from about 250 mg to about 4000 mg. In another embodiment, thedaily oral dose of is from about 500 mg to about 4000 mg. In anotherembodiment, the daily oral dose is from about 750 mg to about 4000 mg.In another embodiment, the daily oral dose is from about 1000 mg toabout 4000 mg. In another embodiment, the daily oral dose is from about1200 mg to about 4000 mg. In another embodiment, the daily oral dose isfrom about 1500 mg to about 4000 mg. In another embodiment, the dailyoral dose is from about 1500 mg to about 3000 mg. In another embodiment,the daily oral dose is from about 1000 mg to about 2000 mg. In anotherembodiment, the daily oral dose is from about 200 mg to about 2000 mg.In another embodiment, the daily oral dose is from about 400 mg to about2000 mg. In another embodiment, the daily oral dose is from about 800 mgto about 2000 mg.

In one particular embodiment the oral dosage form of the currentinvention comprises a therapeutically effective amount of an ester of17-hydroxyprogesterone, wherein, when measured using a USP Type-IIdissolution apparatus in 900 mL of deionized water with 0.5% (w/v) ofsodium lauryl sulfate at 50 RPM at 37° C., the oral dosage form releasesat least 20 wt % of the dose of the ester of 17-hydroxyprogesteroneafter 60 minutes, In another particular embodiment, the dosage formreleases at least about 40 wt % of the dose of the ester of17-hydroxyprogesterone after 60 minutes. In another particularembodiment, the dosage form releases at least about 50 wt % of the doseof the ester of 17-hydroxyprogesterone after 60 minutes. In anotherparticular embodiment, the dosage form releases at least about 70 wt %of the dose of the ester of 17-hydroxyprogesterone after 60 minutes. Ina specific embodiment the ester is 17-hydroxyprogesterone caproate. Inanother embodiment, the dosage form is administered with food.

Following oral administration of the ester of 17-hydroxyprogesterone(e.g. 17-hydroxyprogesterone caproate) in the form of the composition ordosage form the present invention, its concentration in the serum,plasma or blood of the subject may be determined by analyticaltechniques based on radio-immunoassay (RIA), high performance liquidchromatography-Mass Spectroscopy (HPLC-MS/MS) and the like. Accordingly,the plasma or blood levels for the ester may be different. It has to beunderstood that any relative comparisons of blood plasma levels of anycompound should be made with the same assay methodology, or correctionsmust be made to adjust for discrepancy for assay specificity.

Accordingly, in one embodiment, the 17-hydroxyprogesterone caproatecompositions or dosage forms of the present invention can provide a meansteady state 17-hydroxyprogesterone caproate mean C_(max) from about 10ng/mL to about 800 ng/mL, wherein the plasma 17-hydroxyprogesteronecaproate is determined by HPLC-MS/MS method. In a particular embodiment,the compositions or dosage forms provides a mean steady state17-hydroxyprogesterone caproate mean C_(max) from about 10 ng/mL toabout 400 ng/mL.

In further embodiment, the 17-hydroxyprogesterone caproate compositionsor oral dosage forms of the present invention can provide a17-hydroxyprogesterone caproate mean steady state C_(min) of about 1ng/mL or more. The plasma concentrations of the 17-hydroxyprogesteronecaproate can be determined by HPLC-MS/MS method. In one embodiment, thecompositions or oral dosage forms can provide a 17-hydroxyprogesteronecaproate mean steady state C_(min) greater than about 10 ng/mL. Inanother embodiment, the composition or oral dosage forms can provide a17-hydroxyprogesterone caproate mean steady state C_(min) greater thanabout 20 ng/mL, or greater than about 40 ng/ml, greater than about 60ng/mL, or greater than about 80 ng/mL. In one specific embodiment, thecomposition or oral dosage form can provide a mean steady state C_(min)of about 1 to about 60 ng/mL. In another specific embodiment, thecomposition or dosage form can provide a mean steady state C_(min) ofabout 1 ng/mL to about 20 ng/mL.

Accordingly, the oral dosage form of 17-hydroxyprogesterone caproate ofthe present invention can be an immediate release dosage form. In aseparate embodiment, the oral dosage form of the 17-hydroxyprogesteronecaproate of the present invention can be a controlled release dosageform. In another specific embodiment, dosage form can include17-hydroxyprogesterone caproate in the form of both immediate releaseand controlled release fractions, preferably extended or delayed release

Consequently, the controlled release 17-hydroxyprogesterone caproatecompositions or dosage forms of the present invention can provide afluctuation in the 17-hydroxyprogesterone caproate levels less thanabout 795 ng/mL, wherein the fluctuation is determined by the differenceof the mean steady state C_(max) and the mean steady state C_(min) of17-hydroxyprogesterone caproate in plasma or serum or blood, upon oraladministration.

In a another particular aspect, the oral pharmaceutical compositionsand/or dosage forms of 17-hydroxyprogesterone caproate of the currentinvention can be used for the treatment of one or more of the conditionsselected from the group consisting of habitual abortion, recurrentabortion, threatened abortion, post-partum after pains, endometrialcancer, management of primary and secondary amenorrhea, infertility dueto corpus luteum insufficiency, deficiency of progestogen, cervicalinsufficiency, cervical incompetency, and abnormal uterine bleeding. Ina further embodiment, the oral pharmaceutical compositions and/or dosageforms of 17-hydroxyprogesterone caproate of the current invention can beused in for testing endogenous estrogen production, and for theproduction of secretory endometrium and desquamation.

In another embodiment, the oral pharmaceutical compositions and/ordosage forms of 17-hydroxyprogesterone caproate of the current inventioncan be used along with omega-3 fatty acid supplementation to treatsymptomatic preterm labor patients. In a particular embodiment, thecurrent invention compositions and/or dosage forms may include at leastone omega fatty acid. In another particular embodiment, the currentinvention compositions and/or dosage form may include omega-3, omega-6or omega-9 fatty acid or mixtures thereof.

EXAMPLES

The following examples are provided to promote a more clearunderstanding of certain embodiments of the present invention, and arein no way meant as a limitation thereon. Unless otherwise specified ormentioned, all the compositions provided in the examples are withrespect to % w/w of the final composition. Note that with the exceptionof the compositions listed in Examples 1, 7, 10, 17 and 36, the17-hydroxyprogesterone caproate of all other example compositions can bein either treated (milled, micronized, or nanosized) or untreated form.The 17-hydroxyprogesterone Caproate in compositions 1, 7, 10, 17 and 36are untreated for size reduction (i.e. unmilled, non-micronized,un-micronized or non-nanosized), and have an average particle sizegreater than 50 micrometers. The dosage forms of corresponding Exampleswere tested for release of the 17-hydroxyprogesterone caproate using aUSP Type II apparatus, 50 rpm in 900 mL of “simulated intestinal fluidhaving 0.5% w/w sodium lauryl sulfate at 37° C. The percent of the17-hydroxyprogesterone caproate released from each composition wasanalyzed using HPLC.

Examples 1-6 17-hydroxyprogesterone Caproate Compositions

17-hydroxyprogesterone caproate compositions as recited in Examples 1through 6 are prepared by using the respective components shown in TableI. Example 1 is the untreated crystalline form of 17-hydroxyprogesteronecaproate filled into hard gelatin capsule. Example 2 is micronized17-hydroxyprogesterone caproate without a carrier filled into hardgelatin capsule. Examples 3-6, are prepared as follows: The requiredquantities of each of the components of the respective composition,except 17-hydroxyprogesterone caproate are taken in a clean stainlesssteel container and mixed at about 50° C. to 70° C. using a stirrer. Amolten clear-to-hazy mixture is obtained. The required amount of the17-hydroxyprogesterone caproate is added to the clear-to-hazy mixtureand stirred to form a homogenous liquid mixture. A predetermined weightof the resulting liquid mixture is disposed into appropriate sizecapsules according to the 17-hydroxyprogesterone caproate dose required.The capsules are allowed to solidify at room temperature and thenbanded, and packaged into HDPE bottles and sealed with a lid.

The 17-hydroxyprogesterone caproate released from each of thecompositions using the aforementioned dissolution testing parameters areshown in Table I. It should be noted that the Examples 1 & 2(17-hydroxyprogesterone caproate without a carrier) and Examples 3 to 6(17-hydroxyprogesterone caproate admixed with at least one carrier) canbe used for comparison purposes to help illustrate the advantages of thecompositions and dosage forms of the current invention.

TABLE I Example No. 1 2 3 4 5 6 Ingredients Composition in % w/w.17-hydroxyprogesterone 100 100* 12 15 11 18 caproate Lipophilicadditive: — — 53 — 48 — Ex: Castor Oil NF Lipophilic additive: — — 35 —32 — Ex: Lauroglycol FCC Lipophilic additive: — — — 63 — 75 GlycerylMonolinoleate, NF Hydrophilic additive: — — — 16 — — Polyoxyl 40Hydrogenated Castor Oil, NF Hydrophilic additive: — — —  6  9  7 PEG8000 USP % release in 60 mins <10 >70  >70  >70  >70  >70  *micronized17-hydroxyprogesterone caproate (approximate particle size distribution:d100% <25 μm; d50% <15 μm)

The aqueous dispersion of the mixture that includes a lipophilicadditive and a hydrophilic surfactant, if present, of the Examples 3 to6 of Table-I can be hazy to non-clear when viewed with a naked eye.Their absorbance at 400 nm can be greater than 0.1, or greater than 0.3,and/or the particle size of the dispersion can be greater than 100 nm.In some aspects, the average particle size of the dispersion may begreater than 250 nm. Each of the aqueous dispersions is prepared bymixing 1 part of the mixture of the additives of the correspondingexample and 99 parts of an aqueous diluent. The compositions of Example3-6 may be prepared by mixing the additives the 17 hydroxyprogesteronecaproate to get a homogenous solution or suspension. If required, themixture may be heated (for example, to about 40° C. to about 80° C.) toget a solution or to achieve a homogenous suspension. The mixture can bedisposed into a capsule. The dosage form of Example 1 and 2 has17-hydroxyprogesterone caproate in the solid unmicronized and micronizedparticulate form respectively. The 17-hydroxyprogesterone caproate canbe fully solubilized (as in case of Example 3) or partially solubilized(as in case of Examples 5 and 6). The formulations of Table I, ifliquid, can be also formulated to be a solid dosage form by fillingeither as is, or admixed with a solidification aid, into a capsule.Alternatively, they can be formulated into tablets by using appropriatetableting aids.

Examples 7-10 17-hydroxyprogesterone Caproate Compositions

17-hydroxyprogesterone caproate compositions of Examples 7 through 10can be prepared by using the ingredients shown in Table II and attainthe release performance indicated.

TABLE II Example No. 7 8 9 10 Ingredients Composition in % w/w.17-hydroxyprogesterone caproate 90-99 — — 90-99 (particle size > 50 μm)17-hydroxyprogesterone caproate — 70-80 — — micronized*17-hydroxyprogesterone caproate — — 70-80 — (milled) Lactose  1-10  1-20 1-20 30 Povidone K30 3-6 3-6 3-6 3-6 Organic granulating solvent — 0 or0 or q.s*** (example, alcohol)** q.s*** q.s***- % release in 60 mins<15 >50 >50 >30 *may be substituted with nanomilled or nanosized17-hydroxyprogesterone caproate. **removed substantially during dryingprocess ***Quantity sufficient for wet granulation process or for insitu formation/precipitation of fast releasing solid17-hydroxyprogesterone caproate

It should be noted that the compositions of Examples 7 to 10 can beformulated to provide granules for compression into a tablet or fillingin a capsule, sachet etc., with the inclusion of appropriatepharmaceutical aids such as diluents, binder, disintegrant, lubricants,flavor, etc.

Unlike Example 1 and 7, the 17-hydroxyprogesterone caproate releaseprofile of Examples 8, 9 and 10, shown in Table II, illustrate theadvantages of the smaller particle size of 17-hydroxyprogesteronecaproate. These Examples further illustrate the advantages of variousmanufacturing processes, such as granulation, which yield solidcompositions with appropriate 17-hydroxyprogesterone caproate releaseprofiles. In some embodiments, the caproate ester in the compositions ofexamples in Table II can be substituted with other esters of17-hydroxyprogesterone, such as acetate or undecanoate.

Example 11 17-hydroxyprogesterone Caproate Coated Tablets

17-hydroxyprogesterone caproate tablets of Example 7 through 10 can befurther coated with a coating solution having typical composition setforth in Table III, using conventional tablet coating procedures knownin the art to a weight gain of about 3 to 6%.

TABLE III Ingredients Composition in % w/w Polymer (for e.g. 8.0Hypromellose, Methocel E 5) Plasticizer (e.g. Polyethylene 0.6 glycol,NF 8000) Coating Solvent 54.8 (e.g. Ethanol) Coating Solvent 36.6 Water

The coating polymer can be selected based on the need for a specificfunctionality to be imparted to the dosage form. For example filmcoating, taste masking, enteric coating protective coating, sustainedrelease coating and so on can all be used. Unlimited examples of thepolymers for use in such coatings include hypromellose, polyethyleneglycol, povidone, sugars, ethyl celluloses, methacrylates, cellulosephthalates etc. Many conventional coating aids such as talc, starch,plasticizers, opacifiers, colors, flavors etc. can also be used alongwith coating polymers or sugars. The coating solvents can be suitablyvaried based on the coating polymer or sugar being applied.

Examples 12-17 17-hydroxyprogesterone Caproate Compositions

Table IV shows the 17-hydroxyprogesterone caproate compositions ofExamples 12-17 that can be prepared by using the components set forththerein and the method similar to that described for Examples 3-6. Therelease of 17-hydroxyprogesterone caproate from the dosage form is alsoshown in Table IV.

TABLE IV Example No. 12 13 14 15 16 17 Ingredients Composition % w/w17-hydroxyprogesterone 15 15 14 15 22 25 caproate Lipophilic Additive .. . — 85 — — — — (example Glyceryl Caprylate/ Caprate (Capmul ®MCM)Lipophilic Additive (e.g . . . 85 — — — — — Capric Acid) LipophilicAdditive (e.g — 73 65  3  5 Glyceryl Monolinoleate) Hydrophilic Additive(e.g. — — 13 15 — — Polyoxyl 40 Hydrogenated Castor Oil) HydrophilicAdditive (e.g. — — — — — 22 Polyoxyl 35 Castor Oil) Lipophilic Additive(e.g — — —  5 — — Glyceryl Palmitostearate; Glyceryl distearate,Precirol ® ATO 5) Hydrophilic Additive (e.g. — — — — 22 — TocopherolPolyethylene Glycol Succinate) Lipophilic Additive (e.g — — — — 35 48Vitamin E; d,l-α- tocopherol) Hydrophilic Additive (e.g. — — — — 18 —Hypromellose (4,000 cPs) % release in 60 mins >40  >40  >40  >40  >30 >40 

The aqueous dispersion of the mixture of lipophilic additive and thehydrophilic surfactant, if present, in the examples shown in Table-IVcan be hazy to non-clear when viewed with the naked eye. Theirabsorbance at 400 nm can be greater than 0.1, or greater than 0.3,and/or the particle size of the dispersion can be greater than 100 nm.In some aspects, the mean particle size of the dispersion may be greaterthan 250 nm. Each of the aqueous dispersions is prepared by mixing 1part of the mixture of the additives of the corresponding example and 99parts of an aqueous diluent.

The compositions of Table IV, if liquid, can be formulated to be soliddosage forms by filling into a capsule either as is, or admixed with asolidification aid such as polyethylene glycol, glyceryl distearate, waxand the like . . . . It should be noted that these compositions can alsobe formulated to obtain granules for compression into a tablet orfilling into a capsule, sachet etc., with the inclusion of appropriatepharmaceutical aids such as diluents, binders, disintegrants,lubricants, flavors, etc.

The 17-hydroxyprogesterone caproate in the compositions of examples inTable IV can in some embodiments be substituted with other esters of17-hydroxyprogesterone, such as 17-hydroxyprogesterone acetate or17-hydroxyprogesterone undecanoate.

Examples 18-23 17-hydroxyprogesterone Caproate Compositions

Table V shows various 17-hydroxyprogesterone caproate compositions asrecited in Examples 18-23 that can be prepared using the components setforth therein.

TABLE V Example No. 18 19 20 21 22 23 INGREDIENT Composition % w/w17-hydroxyprogesterone 9 7 6 8 8 6 caproate Hydrophilic Surfactant 1 1 14 1 1 (e.g. Tween 80) Hydrophilic Surfactant 4 4 3 1 4 3 (e.g. SodiumLauryl Sulfate) Hydrophilic Polymer — 15 26 5 — 25 (e.g. HPMC) EntericPolymer — — — — — 4 (e.g. Eudragit) Hydrophobic Polymer — — — — 5 —(e.g. Ethyl Cellulose) Diluents/Processing Aids 86 73 64 82 82 61 Total100 100 100 100 100 100Table VI shows various specific embodiments of different dosage forms(DF-1 to DF-9) containing 17-hydroxyprogesterone caproate that can beachieved by various combinations of the compositions shown in Table V.

TABLE VI Compo- sition Dosage Form Exam- DF-1 DF-2 DF-3 DF-4 DF-5 DF-6DF-7 DF-8 DF-9 ple No. Composition % w/w 18 100 50 50 50 30 — — 30 50 19— 50 — — — — — — — 20 — — 50 — — 100 — 30 — 21 — — — 50 — — — 40 50 22 —— — — — — 100 — — 23 — — — — 70 — — — — Total 100 100  100  100  100 100 100 100  100 

-   -   Additional tableting methods known in the art can be used can be        applied to the above exemplified compositions.    -   Excipients shown are exemplary of classes of excipients that can        be used    -   The form of the drug can be interchanged with other forms such        as micronized, sieved, milled, amorphous, nano, etc.        The above dosage forms DF-1 to DF-9 can be single or multiple        particulate units in a capsule or as single or multiple        particulate units compressed into a single tablet or multi-layer        tablets.

Examples 24-28 17-hydroxyprogesterone Caproate Compositions

Table VII shows 17-hydroxyprogesterone caproate compositions as recitedin Examples 24-28 that can be prepared using the components set forththerein, and their release performance.

TABLE VII Example No. 24 25 26 27 28 INGREDIENT Composition (mg perdosage form) 17-hydroxyprogesterone 50 50 50 50 50 HydrophilicSurfactant 2.5 2.5 2.5 2.5 2.5 (e.g. Tween 80) Hydrophilic Surfactant12.5 12.5 12.5 12.5 12.5 (e.g. Sodium Lauryl Sulfate) HydrophilicPolymer 125 65 90 — 3 (e.g. HPMC) Enteric Polymer — — — — 5 (e.g.Eudragit) Coating Processing Aids — — — — 2 (e.g. Plasticizer,Anti-sticking agent) Diluents/Processing Aids 25 25 35 35 35 (e.g.binder, disintegrant, diluent, glidant, lubricant) Total 215 155 190 100110 % Release in 60 minutes >25 >40 >40 100 >30

-   -   Additional tableting methods known in the art can be used can be        applied to the above exemplified compositions.    -   Excipients shown are exemplary of classes of excipients that can        be used, processing aids like binders, disintegrants, diluents,        glidants, lubricants and coating aids commonly known in the art        can be used.    -   The form of the drug can be interchanged with other forms such        as micronized, sieved, milled, amorphous, nano, etc.    -   The above dosage forms can be single or multiple particulate        units in a capsule or as single or multiple particulate units        compressed as a monolithic/matrix tablet or multi-layer tablets        For Example 28 the dosage form is first exposed to about 250 mL        simulated gastric fluid (SGF) without enzyme for the first 30        minutes, followed by exposure to 900 mL of 0.5 wt % SLS in water        at having pH about 6.8.

Examples 29-35 17-hydroxyprogesterone Caproate Compositions

Table VIII shows 17-hydroxyprogesterone caproate compositions andrelease data for Examples 29-35 that can be prepared by using componentsset forth therein and the method similar to that described for Examples12-17.

TABLE VIII Example No. 29 30 31 32 33 34 35 Ingredients Composition %w/w 17- 25 20  7  7  8 16 25 hydroxyprogesterone caproate LipophilicAdditive 48 45 — — — 29 53 (e.g. Benzyl benzoate) Hydrophilic Additive 2  2 — — — —  2 (e.g. Benzyl alcohol) Lipophilic Additive 25 23 — — — —— (e.g. Castor Oil) Lipophilic Additive — — — — 67 — (e.g. Cornglycerides) Lipophilic Additive — — 51 48 — 17 — (e.g. GlycerylCaprylate/Caprate; Capmul ®MCM) Lipophilic Additive — — — — — — — (e.g.Capric Acid) Hydrophilic Additive — 10 42 40 25 38 10 (e.g Polyoxyl 40Hydrogenated Castor Oil) Hydrophilic Additive — — —  5 — — 10 (e.gPolyethylene glycol 8000) % release in 60mins >25  >25  >90* >80  >60  >60  >25  *% released in 30 minutes

The above compositions can be formulated to exhibit immediate orcontrolled release profiles. The aqueous dispersion of the mixture ofthe lipophilic additive and the hydrophilic surfactant, if present, inthe examples of Table-VIII can be hazy to non-clear when viewed with thenaked eye. Their absorbance at 400 nm are greater than 0.1, in somecases greater than 0.3, and/or the average particle size of thedispersion may be greater than 100 nm in some aspects. In other aspects,the average particle size of the dispersion can be greater than 250 nm.Each of the aqueous dispersions is prepared by mixing 1 part of themixture of the additives and surfactants of the corresponding exampleand 99 parts of an aqueous diluent.

As can be seen from the above Examples 29, 30 and 35 by using benzylbenzoate and/or benzyl alcohol, a higher drug loading (e.g. ≧20% w/w17-hydroxyprogesterone caproate) with desired release characteristicscan be achieved. The 17-hydroxyprogesterone caproate can remain fullysolubilized (Examples 29, 30, 31, and 33) or can be partiallysolubilized (Examples 32, 34 and 35) in the compositions. Further, whenviewed with the naked eye the aqueous dispersion of the mixtures havinga lipophilic additive and the hydrophilic surfactant, if present, asrecited in Examples 29-31 and 33-35 can be hazy to non-clear. In somecases, their absorbance at 400 nm is greater than 0.1, or even greaterthan 0.3. Further the average particle size of the dispersion can begreater than 100 nm, or even greater than 250 nm. Each of the aqueousdispersions is prepared by mixing 1 part of the mixture of the additivesand surfactants of the corresponding example and 99 parts of an aqueousdiluent.

The 17-hydroxyprogesterone caproate in the compositions of examples inTable VIII can in some aspects substituted with other esters of17-hydroxyprogesterone, such as 17-hydroxyprogesterone acetate or17-hydroxyprogesterone undecanoate.

The compositions of example 3, 31, 32, 33, and 34 can in some aspects,also be administered as oral liquid. These compositions can also beadministered orally after appropriate admixture/dilution with diluentsuch as water, milk, fruit juices, beverages and the like just beforeadministration.

In certain embodiments, the contents of the above compositions can beadsorbed on some diluents and additional excipients and can be compressinto tablet.

Example 36 17-hydroxyprogesterone Caproate Tablets

17-hydroxyprogesterone caproate containing granules for tableting havingthe components set forth in Table IX can be prepared by wet granulationmethods. Accordingly, 17-hydroxyprogesterone caproate, microcrystallinecellulose and croscarmellose sodium are passed through an ASTM mesh #40mesh sieve and mixed in a low shear granulator to form a uniform blend.A binder solution of Starch 1500 in deionized water can be used togranulate the dry powder blend to a typical granulation end-point. Thewet granulate dried using a tray dryer or fluid air dryer can besized/screened, lubricated with Aerosil 200 and magnesium stearate, andcompressed into tablets.

TABLE IX Ingredients Composition in % w/w 17-hydroxyprogesteronecaproate (untreated) 28 Microcrystalline Cellulose (Avicel PH 102) 52.5Croscarmellose sodium 10 Pregelatinized starch (Starch1500) 8 Colloidalsilicon dioxide (Aerosil 200) 0.5 Magnesium stearate 1The tablets of Example 36 exhibit less than 20% 17-hydroxyprogesteronecaproate released in the first 60 minutes when tested using a USP TypeII apparatus, 50 rpm in 900 mL of simulated intestinal fluid having 0.5%w/w sodium lauryl sulfate at 37° C. Whereas, when the micronized17-hydroxyprogesterone caproate (with particle size d100% being about 50μm or less) with or without surfactant is used in the above formula, atleast 40% release of 17-hydroxyprogesterone caproate may be observedafter the 60 minute time-point.

Examples 37-42 17-hydroxyprogesterone Caproate Compositions

Examples 37-39 of Table X have hydrophilic additives as carriers. TheExamples 37, 38 and 39 therein are prepared by wet granulation processwith organic solvent such as ethanol or ethanol-water as the granulatingliquid. Partial or full amounts of some of hydrophilic additives therein(e.g. povidones, pluronics, surfactants etc.) can be dissolved in thegranulating liquid. Optionally the ester of 17-hydroxyprogesterone (e.g.17-hydroxyprogesterone caproate) can be solubilized or suspended in thegranulating liquid. This granulating liquid can then be poured over theadsorbing hydrophilic carriers (e.g. celluloses, Lactose etc.) with lowshear mixing. The granules can be dried under a gentle current of air atroom temperature. The dried granules are passed through ASTM #40 meshand filled into appropriate size capsules or compressed into tabletsaccording to the required 17-hydroxyprogesterone caproate strength perunit dosage form.

17-hydroxyprogesterone caproate compositions of Examples 40-42 can beprepared by using the components set forth in Table X and according tothe following method: The required quantities of the respective inactivecomponent and the 17-hydroxyprogesterone caproate, are taken in a cleanstainless steel container and mixed gently at about 50° C. to 70° C.using a stirrer, to get a homogenous mixture. A predetermined weight ofthe resulting mixture is disposed into hard gelatin capsule and allowedto solidify at room temperature.

The dosage forms of each Example 37-42 are tested for release of the17-hydroxyprogesterone caproate using a USP Type II apparatus, at 50 rpmin 900 mL of simulated intestinal fluid having 0.5% w/w sodium laurylsulfate at 37° C. The percent of the 17-hydroxyprogesterone caproatereleased from each composition is analyzed using HPLC. The results ofthe release testing are also shown in Table X.

It should be noted that the compositions of Examples 37-42 can beformulated to achieve tablet dosage forms with the inclusion ofappropriate conventional tableting aids such as diluents, binders,disintegrants, lubricants, etc. as needed.

TABLE X Example No. 37 38 39 40 41 42 Ingredients Composition in % w/w17-hydroxyprogesterone 45 40 40 75 34 60 caproate PEG 8000 USP — — — 1029 40 Sodium Lauryl sulfate 10 9 9 10 — — Microcrystalline 45 40 37 — —— Cellulose*, Pluronic F 68 0 11 11 — — — Polyvinylpyrrolidone 0 0 3 537 — (Povidone K 30) % release in 60 mins >40 >40 >40 >40 >40 >30*Magnesium alumnometasilicate (Neuslin ®), lactose and other similarsubstances can be used/calcium silicate

The in vitro 17-hydroxyprogesterone caproate release performance ofExamples 37 to 42 can be seen to be superior over the releaseperformance of the Example 36. It should be noted that in theabove-recited compositions, appropriate amounts of typicalpharmaceutical aids such as glidants, lubricants, anti-adherents,disintegrants and the like, can be incorporated as needed. Further,suitable amounts of hydrophilic release modifying agents (e.g.hypromellose, Eudragits etc.) may also be incorporated as needed in thecompositions of Examples 37 to 42. Also, in some particular cases, whenthe dosage form of the Examples 37 to 42 is a tablet, appropriatefunctional coatings may be applied as required. It should also be notedthat in some aspects the example compositions of Table X can besubstituted with other esters of 17-hydroxyprogesterone (e.g.17-hydroxyprogesterone acetate, 17-hydroxyprogesterone undecanoate,etc.)

Examples 43 and 44 17-hydroxyprogesterone Caproate Compositions

17-hydroxyprogesterone caproate compositions as recited in Examples 43and 44 were prepared by using the components set forth in Table XI. Eachof the compositions was prepared by incorporating 17-hydroxyprogesteronecaproate in the molten mixture of the corresponding inactive componentstaken in a stainless steel container at about 35° C. to 70° C. withgentle stirring to get a free-flowing liquid mixture. A predeterminedweight of the resulting liquid mixture is disposed into hard or softgelatin capsule shells and allowed to solidify at room temperature. Itshould be noted that the liquid mixture can also be allowed to solidifyto room temperature to get solid aggregates which may be sized throughan ASTM mesh #30 to get granular particulates, which can be furtherfilled in hard gelatin capsules or compressed into tablets.

Each of the compositions is tested for release of the17-hydroxyprogesterone caproate using a USP Type II apparatus, at 50 rpmin 900 mL of simulated intestinal fluid having 0.5% w/w sodium laurylsulfate at 37° C. The percent of the 17-hydroxyprogesterone caproatereleased from each composition is analyzed using HPLC. The results ofthe release testing are also shown in Table XI.

TABLE XI Example No. 43 44 Ingredients Composition in % w/w17-hydroxyprogesterone caproate 20 80 Lipophilic additive: 80 20 (e.g.Glycerol esters of C₁₂-C₁₈ fatty acids) % release in 60 mins >30% >30%

Example 45 17-hydroxyprogesterone Caproate Spray Dried Multiparticulates

17-hydroxyprogesterone caproate multiparticulates can be prepared asfollows: 15 g of a milled or micronized 17-hydroxyprogesterone caproateand lactose, mixture (95:5 w/w), are passed through ASTM mesh #60 sieveand added under mixing to about 250 mL of a solution of 8% w/v povidoneK17 in water. The resulting suspension can be spray dried using aconventional spray drying equipment with settings, for example, at aheat inlet temperature of about 60-75° C. and an outlet temperature ofabout 30-38° C., aspirator set at 90-100%, the pump set at about 8-12mL/min, and the flow rate set at about 500-600 L/hr. The final solidmultiparticulate 17-hydroxyprogesterone caproate composition can have acompositional makeup of about 53 wt % 17-hydroxyprogesterone caproate,about 2.8 wt % lactose and about 44.2 wt % povidone K17.

Example 46-50 17-hydroxyprogesterone Caproate Compositions

A mixture of 17-hydroxyprogesterone caproate and the correspondingcomponents can be melted together to get thermosetting fill to bedisposed into capsule. Alternatively, the mixture can be fed into amelt-extruder apparatus for example, a single-screw extruder (Killion,Model KLB 100) equipped with about 1 inch diameter screw and about 6inch flex lip die, and the die opening adjusted to about 0.005 inchesand the screw speed is set at about 50 rpm. The residence time of thematerials within the extruder can be set for about 2 to 8 minutes. Theextruded strands can be cooled to room temperature by passing over achilled roll. The strands can then be sized through an ASTM mesh #40 andthe powder disposed into capsules. The exemplary compositions formelt-extrusion are indicated in Table XII. These dosage forms canrelease 40% or more 17-hydroxyprogesterone caproate in about first 60minutes. It should be noted that the 17-hydroxyprogesterone caproatecompositions of Table XII can be further formulated to include one ormore other substances such as lactose, starches, hydroxypropyl methylcellulose, methacrylate, etc., at varying concentrations from about 12%to about 88% by weight of the total composition either prior tomelt-extrusion or after sizing the melt-extruded composition, in orderto prepare solid multi-particulates for tablets.

TABLE XII Example No. 46 47 48 49 50 Ingredients Composition in %w/w17-hydroxyprogesterone caproate 70 40 50 80 60 Polyethylene glycol 8000USP 10 — 20 15 20 (Glyceryl distearate GDS, 10 40 20 — — Precirol ATO 5)Stearic acid 10 20 10 — Cholesterol — — —  5 20

Example 51 17-hydroxyprogesterone Caproate Compositions Produced byCo-milling

A 17-hydroxyprogesterone caproate containing composition can be preparedby co-milling (or co-grinding) 80 g 17-hydroxyprogesterone caproatealong with 15 g PVP K 17 and 5 g of sodium lauryl sulfate for a periodfrom about 12 hours to about 24 hours using a ceramic ball-millmaintained at about 20±5° C. The co-milled composition can provide asuperior in vitro drug release profile which could be at least 20% morewhen compared to the in vitro release profile of Example 1 when testedusing a USP Type II apparatus, 50 rpm in 900 mL of simulated intestinalfluid having 0.5% w/w sodium lauryl sulfate at 37° C.

Example 52 17-hydroxyprogesterone Caproate Loaded Pellets

17-hydroxyprogesterone caproate coated pellets are prepared using theingredients set forth in Table XIII. A spraying solution of the coatingmaterials can be prepared by dissolving 25 g of 17-hydroxyprogesteronecaproate, 6 g of Pluronic F 68 and 5 g of PVP K 30 in about 250 mL ofdehydrated alcohol. The spray solution can be intermittently sprayed onto a rolling bed of 64 g commercially available microcrystallinecellulose spheres (for example, having a mean particle size in the rangeof about 250 μm to about 600 μm) taken in a conventional coating pan.After all the spray solution is loaded on the spheres, it can be driedunder a gentle current of air for at least 1 hour to remove the solvent.Thus, by adjusting the pan speed, spray rate and the inlet air flow andtemperature, the 17-hydroxyprogesterone caproate loaded pellets or beadscan be obtained which can be disposed into a capsule. Auxiliarypharmaceutical process aids such as talc, starch etc., may be dustedduring the spraying process to avoid agglomeration of the pellets.

It should be noted that appropriate similar or equivalent equipmentknown in the art may be used for the purpose. Also, by varying thequantity of spray solution sprayed on the spheres or by varying theconcentration of 17-hydroxyprogesterone caproate in the spray solution,pellets of different drug loading can be achieved.

TABLE XIII Ingredients Composition in % w/w 17-hydroxyprogesteronecaproate 25 Pluronic F 68 6 Polyvinylpyrrolidone K 30 5 DehydratedAlcohol 250 mL Microcrystalline cellulose spheres Celsphere ®) 64

Example 53 17-hydroxyprogesterone Caproate Suspension Compositions

A homogenous suspension of 17-hydroxyprogesterone caproate prepared in aliquid vehicle having at least one non-solvent can be made byconventional processes known in the art. The suspension can be dosed asa conventional oral liquid or a known volume of the suspension may beencapsulated. Pharmaceutical aids such suspending agents, thickeningagents or viscosity modifiers, wetting agents, etc., known in the artcan be used to achieve homogenous suspension of the drug in the liquidvehicle.

Example 54 17-hydroxyprogesterone Caproate Composition in vivoEvaluation

A preliminary pharmacokinetic evaluation upon oral administration of17-hydroxyprogesterone caproate of the current invention was carried outin male dogs. A single oral dose of 30 mg/kg and 5 mg/kg of17-hydroxyprogesterone caproate formulated in a accordance withexemplary formulations of the present invention were used for relativebioavailability study in a fed state, compared with an intramusculardose of 6.4 mg/kg (composition similar to commercially availableIntramuscular Injection, Makena®) as positive control.

The post-dose blood levels of 17-hydroxyprogesterone caproate weremonitored for 24 hours after oral dosing and for 192 hours afterintramuscular injection dosing. About 2 mL of blood was drawn from thejugular, cephalic, or saphenous veins immediately before the dose wasadministered and at pre-determined intervals post-dose. At each timepoint, the blood sample was collected in a vacutainer tubes andcentrifuged at about 3200 rpm for approximately 10 minutes at about 5°C. The serum obtained was analyzed by HPLC-MS/MS for17-hydroxyprogesterone caproate. The results of the17-hydroxyprogesterone caproate concentration in the samples are shownin Table-XIV below:

TABLE XIV Exemplary Oral Dosage formulations IM of the present inventionInjection Dose Administered 30 mg/kg 5 mg/kg 6.4 mg/kg Mean C_(last)(ng/mL) 4.51 0.28 2.54 C_(avg) (ng/mL) 74 2.5 8 Mean AUC_(0-last)(ng*h/mL) 1767 60 1546 AUC(ng*h mL⁻¹)_(0-24 h)/Dose 5.8 1.0 — (mg) Ratio

Contrary to reports in the literature we surprisingly found that oralcompositions of the present invention provided significant blood levels(C_(avg)) of 17-hydroxyprogesterone caproate upon oral administration.

Numerous modifications and alternative arrangements may be devised bythose skilled in the art without departing from the spirit and scope ofthe present invention and the appended claims are intended to cover suchmodifications and arrangements. Thus, while the present invention hasbeen described above with particularity and detail in connection withwhat is presently deemed to be the most practical and preferredembodiments of the invention, it will be apparent to those of ordinaryskill in the art that variations including, but not limited to,variations in size, materials, shape, form, function and manner ofoperation, assembly and use may be made without departing from theprinciples and concepts set forth herein.

What is claimed is:
 1. A method of treating a female with apharmaceutical composition said method comprising: orally administeringa tablet or capsule pharmaceutical composition comprising17-hydroxyprogesterone caproate and a pharmaceutically acceptablecarrier to said female in an amount sufficient to provide about 750 mgto about 4000 mg of 17-hydroxyprogesterone caproate per day, whereinsaid pharmaceutical composition when measured using a USP Type-IIdissolution apparatus in 900 mL of simulated intestinal fluid having0.5% w/w sodium lauryl sulfate at 50 RPM at 37° C., releases at least20% of the 17-hydroxyprogesterone caproate at 60 minutes and saidpharmaceutical composition comprises 17-hydroxyprogesterone caproatewith a mean particulate diameter of 50 micron or less.
 2. The method ofclaim 1, wherein said female is a pregnant female.
 3. The method ofclaim 1 wherein said amount sufficient to provide is about 800 mg to2000 mg of 17-hydroxyprogesterone caproate per day.
 4. The method ofclaim 1, wherein said administering is twice or three times daily. 5.The method of claim 1, wherein said female is a pregnant female with aprior history of preterm birth.
 6. The method of claim 1, wherein saidpharmaceutical composition upon single dose administration provides anAUC/dose ratio for 17-hydroxyprogesterone caproate of about 10 or less.7. The method of claim 1, wherein said pharmaceutical composition uponsingle dose administration provides a ratio of the17-hydroxyprogesterone caproate AUC(0-24 h) to dose of the17-hydroxyprogesterone caproate administered can be about 0.2 ng*hmL⁻¹mg⁻¹ to about 10 ng*h mL⁻¹mg⁻¹.
 8. The method of claim 1, whereinsaid pharmaceutical composition is formulated as a powder, granulate,particulate, bead, pellet, sprinkle, suspension, solution, or acombination thereof.
 9. The method of claim 1, said pharmaceuticalcomposition comprising an amount of 17-hydroxyprogesterone caproateequivalent to about 10 mg to about 800 mg of 17-hydroxyprogesterone. 10.The method of claim 1, said pharmaceutical composition comprising ahydrophilic additive.
 11. The method of claim 1, said pharmaceuticalcomposition comprising a lipophilic additive.
 12. The method of claim 1,said pharmaceutical composition comprising a hydrophilic ionic ornon-ionic surfactant.
 13. The method of claim 1, said pharmaceuticalcomposition comprising micronized, sieved, milled, amorphous, ornanosized 17-hydroxyprogesterone caproate.
 14. The method of claim 1,said pharmaceutical composition having 17-hydroxyprogesterone caproatethat is fully solubilized, partially solubilized or particulate.
 15. Themethod of claim 1, said pharmaceutical composition having17-hydroxyprogesterone caproate with a mean particulate diameter of 25micron or less.
 16. The method of claim 1, said pharmaceuticalcomposition having 17-hydroxyprogesterone caproate with a meanparticulate diameter of 1 micron or less.
 17. A method of treating apregnant human female, with a pharmaceutical composition said methodcomprising: orally administering, with food, a tablet or capsulepharmaceutical composition comprising 17-hydroxyprogesterone caproateand a pharmaceutically acceptable carrier to a pregnant human female,wherein said pharmaceutical composition when measured using a USPType-II dissolution apparatus in 900 mL of simulated intestinal fluidhaving 0.5% w/w sodium lauryl sulfate at 50 RPM at 37° C., releases atleast 20% of the 17-hydroxyprogesterone caproate at 60 minutes and saidpharmaceutical composition comprises 17-hydroxyprogesterone caproatewith a mean particulate diameter of 50 micron or less.
 18. A method oftreating a pregnant human female with a pharmaceutical composition saidmethod comprising: orally administering a tablet or capsulepharmaceutical composition comprising 17-hydroxyprogesterone caproateand a pharmaceutically acceptable carrier to a pregnant human female inan amount sufficient to provide about 750 mg to about 4000 mg of17-hydroxyprogesterone caproate per day, said method reducing the riskof preterm birth in the pregnant human female, wherein saidpharmaceutical composition when measured using a USP Type-II dissolutionapparatus in 900 mL of simulated intestinal fluid having 0.5% w/w sodiumlauryl sulfate at 50 RPM at 37° C., releases at least 20% of the17-hydroxyprogesterone caproate at 60 minutes and said pharmaceuticalcomposition comprises 17-hydroxyprogesterone caproate with a meanparticulate diameter of 50 micron or less.
 19. The method of claim 17,said pharmaceutical composition comprising a hydrophilic additive orlipophilic additive.
 20. The method of claim 18, said pharmaceuticalcomposition comprising a hydrophilic additive or lipophilic additive.21. The method of claim 17, said pharmaceutical composition comprising ahydrophilic ionic or non-ionic surfactant.
 22. The method of claim 18,said pharmaceutical composition comprising a hydrophilic ionic ornon-ionic surfactant.
 23. The method of claim 17, said tablet or capsulecomprising an amount of 17-hydroxyprogesterone caproate equivalent toabout 10 mg to about 800 mg of 17-hydroxyprogesterone.
 24. The method ofclaim 17, said pharmaceutical composition comprising micronized, sieved,milled, amorphous, or nanosized 17-hydroxyprogesterone caproate.
 25. Themethod of claim 17, wherein said administering is twice or three timesdaily.
 26. The method of claim 18, said tablet or capsule comprising anamount of 17-hydroxyprogesterone caproate equivalent to about 10 mg toabout 800 mg of 17-hydroxyprogesterone.
 27. The method of claim 18, saidpharmaceutical composition comprising micronized, sieved, milled,amorphous, or nanosized 17-hydroxyprogesterone caproate.
 28. The methodof claim 18, wherein said administering is twice or three times daily.